CN114606227A - High-precision adenine base editor and application thereof - Google Patents

High-precision adenine base editor and application thereof Download PDF

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CN114606227A
CN114606227A CN202210163391.3A CN202210163391A CN114606227A CN 114606227 A CN114606227 A CN 114606227A CN 202210163391 A CN202210163391 A CN 202210163391A CN 114606227 A CN114606227 A CN 114606227A
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黄强
朱海霞
杜文豪
姜欣怡
秦琴
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Abstract

The invention discloses a high-precision adenine base editor and application thereof. The adenine base editor of the present invention is obtained by designing and replacing the linker between SpCas9(D10A) and deaminase TadA of wild-type adenine base editor ABE8e from the beginning. These high-precision adenine base editors not only greatly shorten the length of the linker, but also have gene editing activity at the target site comparable to or even higher than that of wild-type ABE8 e. And the adenine base editors greatly reduce the editing window of the wild ABE8e, effectively improve the editing precision of ABE8e and ensure that the editing is more accurate. Therefore, the six high-precision adenine base editors have greater application potential in precise gene editing of biological medicines.

Description

High-precision adenine base editor and application thereof
Technical Field
The invention belongs to the technical field of protein engineering, and particularly relates to an adenine base editor and application thereof.
Background
How to accurately and efficiently perform gene editing has been an important goal in the field of life sciences. In recent years, it has been found that CRISPR nucleases can achieve the goal of genome modification by stimulating cell repair by inducing double-stranded DNA breaks (DSBs). However, DSB-initiated repair of non-homologous end joining (NHEJ) is often not controlled by human intervention, and can result in gene Indels (Indels) by deletion, replication or other DNA rearrangements (2). Addition of donor DNA template can stimulate homeologously-directed repair (HDR) to replace DNA alleles with precision, but this process is mainly limited to dividing cells (3). Therefore, it is urgently required to develop an editing technique for precisely modifying DNA without inducing DSB (4).
To address this need, David r. Generally, the base editor consists of a Cas protein (nickaseCas, nCas) that retains single-strand cleavage activity and a deaminase. After binding to the target site of the DNA, base pairing between the guide RNA (sgRNA) and the target DNA strand (target DNA, TS) results in the replacement of a short non-target DNA strand (NTS) in the "R loop", followed by deaminase modification of the bases within the ssDNA to create a mutation (6). To increase editing efficiency in eukaryotic cells, single-stranded nickases also nick unedited DNA strands, inducing cells to repair the unedited strands using the edited strands as templates (7).
Currently, two types of DNA base editors have been characterized: a Cytosine Base Editor (CBE) for converting the C.G base pair to a T.A base pair, and an Adenine Base Editor (ABE) for converting the A.T base pair to aConversion to G.C base pairs (8, 9). However, current CBE editing is inefficient and highly site-dependent, and their use is therefore severely limited (7). In contrast, ABE appears more important because it can correct 47% of disease-associated point mutations in the ClinVar database (4). Liu et al evolved fusion of e.coli tRNA adenosine deaminase (wtTadA) and Cas9 to ABE8e that catalyzes adenosine deamination by directed evolution to obtain the ABE system, which encodes a TadA-linker-SpCas 9(D10A) complex, wherein TadA is the evolved wtTadA variant, responsible for substrate DNA editing; linker is (SGGS)2-XTEN-(SGGS)2The linker sequence of (a) responsible for linking the two domains SpCas9(D10A) and TadA; SpCas9(D10A) retained the activity of a single-stranded nickase, responsible for targeting the target sequence under the guidance of sgrnas (10). As a high-compatibility base editing tool, ABE8e has wide application prospect.
Although ABE8e is a powerful gene editing tool, there are many problems to be solved, the biggest problem limiting its further application is that ABE8e can edit any a in the four to five nucleotide window in the substrate DNA, i.e. the fourth to eighth nucleotides distal to the PAM, whereas a outside the editing target site introduces unwanted products, leading to deleterious mutations (9). In order to solve the problems, a linker between SpCas9(D10A) and TadA is designed from the beginning, six high-precision ABE8e mutants with obviously reduced editing windows are obtained, namely 4L-ABE8e, 4P-ABE8e, 6L-ABE8e, 7L-ABE8e, 7P-ABE8e and 12EK-ABE8e, so that a plurality of high-precision gene editing tools are provided for a gene editing library.
Disclosure of Invention
The purpose of the present invention is to provide a plurality of adenine base editors having high precision and high editing activity, and use thereof.
The invention provides a high-precision adenine base editor, the editing window of which is narrower than that of a wild-type adenine base editor ABE8e, namely the editing accuracy is higher, in particular, the invention respectively replaces 177-208 amino acids of a linker of 32 amino acids of the wild-type adenine base editor ABE8e with ETRS and NKTYPP、TTEPPDN、PAPA、PAPAPAP、A(EAAAK)2The DNA fragments obtained after A are recombined and respectively marked as 4L-ABE8e, 4P-ABE8e, 6L-ABE8e, 7L-ABE8e, 7P-ABE8e and 12EK-ABE8e, and belong to a base editing system.
Under the same reaction condition, the 4L-ABE8e, 4P-ABE8e, 6L-ABE8e, 7L-ABE8e, 7P-ABE8e and 12EK-ABE8e have the same or higher shearing activity with wild-type ABE8 e.
Under the same reaction conditions, the editing windows of the 4L-ABE8e, the 4P-ABE8e, the 6L-ABE8e, the 7L-ABE8e, the 7P-ABE8e and the 12EK-ABE8e are smaller than those of the wild-type ABE8e, and the editing precision is higher.
The nucleotide sequence and the amino acid sequence of the wild ABE8e are respectively shown in SEQ ID NO.1 and SEQ ID NO. 2;
the nucleotide sequences of the high-precision adenine base editors, namely 4L-ABE8e, 4P-ABE8e, 6L-ABE8e, 7L-ABE8e, 7P-ABE8e and 12EK-ABE8e are respectively shown as SEQ ID NO.3, SEQ ID NO.5, SEQ ID NO.7, SEQ ID NO.9, SEQ ID NO.11 and SEQ ID NO.13, the amino acid sequences are respectively shown as SEQ ID NO.4, SEQ ID NO.6, SEQ ID NO.8, SEQ ID NO.10, SEQ ID NO.12 and SEQ ID NO.14, and the similarity with the wild-type ABE8e is more than 90%.
The invention also provides an expression vector containing the polynucleotide sequence.
The invention also provides a host cell which can be used for transforming the expression vector.
The invention also provides a preparation method of the high-precision adenine base editor, which comprises the following specific steps: firstly, constructing a polynucleotide sequence expression vector of the high-precision adenine base editor; then, the expression vector is transformed into a host cell, and a single clone is screened and selected; and finally, inducing and expressing the monoclonal antibody, and separating the high-precision adenine base editor from an expression product by an affinity chromatography and molecular sieve method.
The high-precision adenine base editor, the polynucleotide sequence and the expression vector provided by the invention can be used as an editing tool for editing genomic DNA and are used for related editing of genomic DNA fragments.
In the invention, the gene editing is multi-site editing with more than two editing sites; the means for editing is base conversion of adenine (A) to guanine (G).
In the present invention, the high-precision adenine base editor comprises a guide sgRNA matched to a target DNA fragment as an editing tool.
The high-precision adenine base editor can be combined with sgRNA which mediates the high-precision adenine base editor, so that a target gene can be edited.
In the invention, the vector containing the polynucleotide sequence for coding the high-precision adenine base editor is transferred into a host cell together with a guide sgRNA matched with the vector, and the gene is edited.
In the present invention, the base transition from adenine (A) to guanine (G) at the multiple sites is a base transition from adenine (A) to guanine (G) by deamination of adenine (A) with an adenine base editor and repair of a mismatch between duplexes with a repair system of a host cell.
Compared with the prior art, the high-precision adenine base editor belongs to a base editing system, has the characteristics of high activity, high precision and the like, can realize precise editing of a specific position of a genome in a human body, and has potential biomedical application value.
Drawings
FIG. 1 is the domain composition of wild-type ABE8e and six high precision adenine base editors.
FIG. 2 shows the monoclonal screening and bacterial culture.
FIG. 3 shows the principle of protein purification by nickel column affinity chromatography
FIG. 4 shows a process for purifying a target protein.
FIG. 5 shows the result of SDS-PAGE electrophoresis of the target protein.
FIG. 6 shows the results of in vitro editing window and editing activity test of the target protein.
Detailed Description
The invention is further described below by means of specific examples.
The experimental procedures used in the following examples are, unless otherwise specified, conventional procedures.
Materials, reagents and the like used in the following examples are all commercially available unless otherwise specified.
High-precision adenine base editor
The six high-precision adenine base editors of the invention are characterized in that the linker of 32 amino acids, namely 177 to 208 amino acids of the wild-type adenine base editor ABE8e are respectively replaced by ETRS, NKTYPP, TTEPPDN, PAPA, PAPAPAP and A (EAAAK)2The recombinant proteins obtained after A are respectively marked as 4L-ABE8e, 4P-ABE8e, 6L-ABE8e, 7L-ABE8e, 7P-ABE8e and 12EK-ABE8e, as shown in figure 1. The six high-precision adenine base editors not only have gene editing activity equivalent to that of wild-type ABE8e, but also have a narrower editing window and higher editing precision, so that more precise in vivo targeted editing can be realized.
Second, polynucleotide sequence for coding high-precision adenine base editor
Transcribing and translating said polynucleotide sequence comprising DNA or RNA of said high precision adenine base editor. DNA can also be subdivided into plasmid DNA, genomic DNA or artificially synthesized DNA.
The polynucleotide sequence encoding the high-precision adenine base editor may be prepared using related molecular biology techniques familiar to those skilled in the art or scientific research, and is not limited to recombinant DNA techniques and chemical synthesis methods.
Expression vector
The expression vector contains a polynucleotide sequence encoding the high-precision adenine base editor. The expression vector can be constructed by scientific research or molecular biology methods familiar to the skilled person, including DNA recombination technology, DNA synthesis technology and the like, the DNA of a high-precision adenine base editor is mainly and effectively connected to a cloning site on the vector, and then target proteins 4L-ABE8e, 4P-ABE8e, 6L-ABE8e, 7L-ABE8e, 7P-ABE8e and 12EK-ABE8e are expressed through processes of transcription, translation and the like.
Fourth, host cell
The host cell is a recombinant plasmid for transforming and expressing a high-precision adenine base editor. Mainly comprises prokaryotic cells (such as bacteria), lower eukaryotic cells (such as yeast), higher eukaryotic cells (such as mammalian cells) and the like. Commonly used host cells are, for example, E.coli DH5 alpha, Rosetta (DE3), HEK293, CHO, Hela cells and the like.
Five, high precision adenine base editor and its coding nucleotide sequence and use of said expression vector
The high-precision adenine base editor, the polynucleotide sequence for coding the enzyme and the expression vector can be used for editing genome DNA fragments or preparing gene editing tools. The high-precision adenine base editor is a multi-site editor in which the editing means is the base conversion from adenine (A) to guanine (G).
Sixth, gene editing tool and method thereof
The gene editing tool belongs to a base editing system, a high-precision adenine base editor can deaminate adenosine (A) into inosine (I) under the guidance of a specific sgRNA in an editing window, and DNA replicase recognizes the inosine (I) into guanosine (G), so that subsequent DNA replication is carried out by taking the guanosine (G) as a template, thereby completing the base conversion from A to G. The editing process may be performed in vitro or in vivo.
As exemplified in some embodiments of the invention, a high precision adenine base editor can cleave substrate DNA (920bp) in vitro under the guidance of sgrnas.
In the present invention, a high-precision adenine base editor can be used as an abbreviation for 4L-ABE8e, 4P-ABE8e, 6L-ABE8e, 7L-ABE8e, 7P-ABE8e and 12EK-ABE8e, and has the same meaning as that of 4L-ABE8e, 4P-ABE8e, 6L-ABE8e, 7L-ABE8e, 7P-ABE8e and 12EK-ABE8 e. The six high-precision adenine base editors of the invention respectively replace the linker of 32 amino acids, namely 177 to 208 amino acids of wild ABE8e, into ETRS, NKTYPP, TTEPPDN, PAPA, PAPAPAP and A (EAAAK)2And A is obtained through recombination.
Before the present embodiments are further described, it is to be understood that the scope of the invention is not limited to the particular embodiments described below, and that the terminology used in the examples herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the scope of the invention. The test methods in the examples below, in which the specific conditions are not specified, were generally conducted under the conventional conditions or under the conditions recommended by the respective manufacturers.
In the numerical ranges given in the examples, it is to be understood that both endpoints of each numerical range, and any number between the endpoints, are interchangeable unless the invention otherwise specifically states. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition to the specific methods, devices, and materials used in the examples, any methods, devices, and materials similar or equivalent to those described in the examples may be used in the practice of the invention in addition to the specific methods, devices, and materials used in the examples, in keeping with the knowledge of one skilled in the art and with the description of the invention.
Unless otherwise indicated, the experimental methods, detection methods, and preparation methods disclosed herein all employ conventional techniques in the art of molecular biology, biochemistry, recombinant DNA technology, and related fields.
Example 1 construction of plasmid for high-precision adenine base editor
1. Construction of mutants
Using wild ABE8e (base sequence SEQ ID NO.1 and amino acid sequence SEQ ID NO. 2) as template, and respectively replacing 177-208 amino acids of amino acid sequence with ETRS, NKTYPP, TTEPPDN, PAPA, PAPAPAP, A (EAAAK)2A, thereby producing 4L-ABE8e, 4P-ABE8e, 6L-ABE8e, 7L-ABE8e, 7P-ABE8e and 12EK-ABE8e, respectively, as shown in FIG. 1. The detailed steps are briefly described as follows:
the primers are mainly used for carrying out conventional PCR amplification, and then the template is digested to obtain the DNA fragment. The primers of 4L-ABE8e, 4P-ABE8e, 6L-ABE8e, 7L-ABE8e, 7P-ABE8e and 12EK-ABE8e are SEQ ID NO.15-16, SEQ ID NO.17-18, SEQ ID NO.19-20, SEQ ID NO.21-24, SEQ ID NO.25-28 and SEQ ID NO.29-32, respectively, and all the primers are ordered from Shanghai Bioengineering Co., Ltd.
(1) Use of
Figure BDA0003515646430000051
GXL DNA Polymerase was subjected to PCR amplification, and the reaction system and reaction parameters were as follows:
an enzyme digestion reaction system:
Figure BDA0003515646430000061
reaction conditions are as follows:
Figure BDA0003515646430000062
after the PCR is finished, the plasmid template needs to be digested by adding digestive enzyme provided by the kit, and the reaction system is as follows:
Figure BDA0003515646430000063
after mixing well, the mixture was reacted at 37 ℃ for 1 hour. Finally, the PCR product was transformed into E.coli DH 5. alpha. and single clones were selected after overnight culture.
(2) Sample sequencing
Sequencing of single clones was performed by one generation sequencing by Shanghai Jili Biotechnology Ltd. After the sequencing is successful, the target plasmid is transformed into Rosetta (DE3) cells, and the amplification culture of bacterial liquid and the expression and purification of the target protein are carried out.
Example 2 preparation of high-precision adenine base editor
2. Protein expression and purification
2.1 protein expression
(1) Opening the super clean bench, wiping the table top and various appliances and consumables with cotton ball containing 75% alcohol, starting the ultraviolet lamp for 20min, and starting the fan for standby.
(2) 10. mu.l of the inoculum was pipetted into 6ml of LB broth containing the double antibody (Amp and Cm) and cultured overnight at 37 ℃ with shaking at 200 r/min.
(3) The overnight cultured broth was transferred to 800ml LB (purchased from Biotech) liquid medium containing double antibody at a volume ratio of 1:100, and cultured at 37 ℃ with shaking at 200 r/min. And detecting the OD value of the bacterial liquid at any time in the culture process.
(4) When the OD value of the bacterial liquid is close to 0.8-1, adding a protein inducer IPTG to enable the final concentration to be 0.1mM, and then carrying out shake culture at 20 ℃ at 200r/min for 12 h.
(5) Collecting bacterial liquid, centrifuging at 5000r/min for 5min to precipitate thallus, discarding supernatant, and weighing thallus.
2.2 protein purification
The protein purification is mainly carried out by a nickel column affinity chromatography technology, as shown in figure 3; the purification process comprises the steps of thallus crushing, protein sample centrifugal collection, protein sample and nickel column medium co-incubation, target protein elution and the like, and is shown in figure 4. The detailed steps are as follows:
(1) 15ml of balance liquid (20mM HEPES,500mM KCl, pH7.5) which is pre-iced in ice bath and has PMSF of final concentration of 0.1mM is added into 3g of the thalli, a vortex instrument is used for resuspending to disperse and mix fungus blocks evenly, a cell ultrasonic crusher is used for crushing cells, ultrasonic treatment is carried out for 3sec and 5sec, one time is carried out for 10min, and the ultrasonic treatment is carried out twice, wherein the ultrasonic treatment is carried out in ice bath.
(2) And centrifuging the crushed bacterial liquid at 4 ℃ and 10000rpm for 45-60 min, and collecting the supernatant.
(3) The supernatant and the balance solution treated Qiagen Ni-NTA medium oscillation incubation for 90min, then standing for 30min, waiting Qiagen Ni-NTA settlement.
(4) Qiagen Ni-NTA was loaded onto a gravity column, washed with equilibration and elution (20mM HEPES,500mM KCl,500mM imidazole, pH7.5) gradients (20, 30, 40, 50, 100, 250, 500mM imidazole) at a flow rate of 2ml/min, respectively, under the monitoring of the BioLogic LP system, and proteins were collected.
(5) And (3) carrying out SDS-PAGE identification on protein solutions eluted by different imidazole concentrations, and observing the expression and the hanging column effect of the target protein.
The purification results of wild-type ABE8e, 4L-ABE8e, 4P-ABE8e, 6L-ABE8e, 7L-ABE8e, 7P-ABE8e and 12EK-ABE8e of the proteins are shown in FIG. 5, which shows the purification situation of the target protein. As shown in the figure, the bands of the hetero-protein are less, indicating that the target protein is purer.
Example 3 detection of editing Window and editing Activity of high-precision adenine base editor
3. Activity detection
To detect the editing window of the adenine base editor with high precision, we designed DNA (SEQ ID NO.33-SEQ ID NO.37) and sgRNA (SEQ ID NO.38-SEQ ID NO.42) targeting the fourth to eighth adenine (A) ends of PAM, respectively
Figure BDA0003515646430000081
The reaction system is mixed according to the proportion of ABE8e related protein sgRNA to DNA 200nM to 40nM, and the specific ratio is as follows:
Figure BDA0003515646430000082
the reaction system was incubated at 37 ℃ for two hours, and then the reacted DNA was purified using an ultra-thin DNA product purification kit (purchased from Tiangen Biochemical technology Co., Ltd.), followed by incubation at 37 ℃ for one hour with EndoV enzyme according to the following reaction system:
Figure BDA0003515646430000083
the enzyme EndoV specifically recognizes inosine (I) and cleaves downstream thereof, and adenosine (A) deaminates to inosine (I) when deamination occurs, whereby double strand break of DNA occurs upon addition of the enzyme EndoV. And finally detecting the in vitro editing window and editing activity of the high-precision adenine base editor by agarose gel electrophoresis. As shown in fig. 6, compared with wild-type ABE8e, 4L-ABE8e retains 5A editing activity and reduces activity on other a sites, thereby greatly reducing the editing window of ABE8e and improving editing accuracy; the 6L-ABE8e, the 4P-ABE8e, the 7P-ABE8e and the 12EK-ABE8e reduce the editing activity of the 6A-8A locus and simultaneously improve the editing activity of the 4A-5A locus, thereby not only improving the editing precision, but also improving the editing activity. In conclusion, the high-precision adenine base editor has smaller editing window and higher editing precision while retaining the shearing activity equivalent to that of the wild-type ABE8e, and is expected to become a gene editing tool with potential application value in the field of precise biomedical medicine.
Reference to the literature
1.M.Jinek et al.,A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity.Science337,816-821(2012).
2.J.R.Chapman,M.R.Taylor,S.J.Boulton,Playing the end game:DNA double-strand break repair pathway choice.Mol.Cell47,497-510(2012).
3.D.Paquet et al.,Efficient introduction of specific homozygous and heterozygous mutations using CRISPR/Cas9.Nature533,125-129(2016).
4.M.J.Landrum et al.,ClinVar:public archive of relationships among sequence variation and human phenotype.Nucleic Acids Res.42,D980-985(2014).
5.H.A.Rees,D.R.Liu,Base editing:precision chemistry on the genome and transcriptome of living cells.Nat.Rev.Genet.19,770-788(2018).
6.T.P.Huang,G.A.Newby,D.R.Liu,Precision genome editing using cytosine and adenine base editors in mammalian cells.Nat.Protoc.16,1089-1128(2021).
7.K.Nishida et al.,Targeted nucleotide editing using hybrid prokaryotic and vertebrate adaptive immune systems.Science353,6305(2016).
8.A.C.Komor,Y.B.Kim,M.S.Packer,J.A.Zuris,D.R.Liu,Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage.Nature533,420-424(2016).
9.N.M.Gaudelli et al.,Programmable base editing of A·T to G·C in genomic DNA without DNA cleavage.Nature551,464-471(2017).
10.M.F.Richter et al.,Phage-assisted evolution of an adenine base editor with improved Cas domain compatibility and activity.Nat.Biotechnol.38,883-891(2020)。
Sequence listing
<110> university of Compound Dan
<120> high-precision adenine base editor and application thereof
<160> 42
<170> SIPOSequenceListing 1.0
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atgggcagca gccatcatca tcatcatcac tcggaggtcg agttttcaca tgagtattgg 60
atgcgtcatg ccttgacgtt ggcgaaacgg gcgcgcgatg agcgtgaggt gcccgtggga 120
gcggtgttgg tactgaataa ccgggttata ggggaaggat ggaaccgggc tattgggtta 180
cacgacccaa cggcgcacgc cgagataatg gcactgcgcc aagggggctt agttatgcag 240
aattatcgcc ttatcgatgc tacactgtat gtaacctttg aaccctgcgt aatgtgtgcg 300
ggggctatga tccactcgag aatagggcgc gtggtattcg gcgtacgcaa cagcaaacgt 360
ggggctgcgg gctcgttgat gaacgttctg aactaccccg gaatgaatca cagagtagag 420
atcacggagg gaattttggc cgacgaatgt gcagctttac tgtgcgattt ttatcggatg 480
ccgcggcaag tcttcaacgc acagaagaag gctcaatctt ccattaactc aggtggctcg 540
agtggtggga gtagcggatc tgagacgcca ggcacatcag agagtgcaac ccccgagtca 600
tcgggtggga gttccggcgg atctgataag aaatactcaa taggcttagc tatcggcaca 660
aacagcgtcg gctgggccgt cattacggac gagtacaagg tgccgagcaa aaaattcaaa 720
gttctgggca ataccgatcg ccacagcata aagaagaacc tcattggcgc cctcctgttc 780
gactccgggg agacggccga agccacgcgg ctcaaaagaa cagcacggcg cagatatacc 840
cgcagaaaga atcggatctg ctacctgcag gagatcttta gtaatgagat ggctaaggtg 900
gatgactctt tcttccatag gctggaggag tcctttttgg tggaggagga taaaaagcac 960
gagcgccacc caatctttgg caatatcgtg gacgaggtgg cgtaccatga aaagtaccca 1020
accatatatc atctgaggaa gaagcttgta gacagtactg ataaggctga cttgcggttg 1080
atctatctcg cgctggcgca tatgatcaaa tttcggggac acttcctcat cgagggggac 1140
ctgaacccag acaacagcga tgtcgacaaa ctctttatcc aactggttca gacttacaat 1200
cagcttttcg aagagaaccc gatcaacgca tccggagttg acgccaaagc aatcctgagc 1260
gctaggctgt ccaaatcccg gcggctcgaa aacctcatcg cacagctccc tggggagaag 1320
aagaacggcc tgtttggtaa tcttatcgcc ctgtcactcg ggctgacccc caactttaaa 1380
tctaacttcg acctggccga agatgccaag cttcaactga gcaaagacac ctacgatgat 1440
gatctcgaca atctgctggc ccagatcggc gaccagtacg cagacctttt tttggcggca 1500
aagaacctgt cagacgccat tctgctgagt gatattctgc gagtgaacac ggagatcacc 1560
aaagctccgc tgagcgctag tatgatcaag cgctatgatg agcaccacca agacttgact 1620
ttgctgaagg cccttgtcag acagcaactg cctgagaagt acaaggaaat tttcttcgat 1680
cagtctaaaa atggctacgc cggatacatt gacggcggag caagccagga ggaattttac 1740
aaatttatta agcccatctt ggaaaaaatg gacggcaccg aggagctgct ggtaaagctt 1800
aacagagaag atctgttgcg caaacagcgc actttcgaca atggaagcat cccccaccag 1860
attcacctgg gcgaactgca cgctatcctc aggcggcaag aggatttcta cccctttttg 1920
aaagataaca gggaaaagat tgagaaaatc ctcacatttc ggatacccta ctatgtaggc 1980
cccctcgccc ggggaaattc cagattcgcg tggatgactc gcaaatcaga agagaccatc 2040
actccctgga acttcgagga agtcgtggat aagggggcct ctgcccagtc cttcatcgaa 2100
aggatgacta actttgataa aaatctgcct aacgaaaagg tgcttcctaa acactctctg 2160
ctgtacgagt acttcacagt ttataacgag ctcaccaagg tcaaatacgt cacagaaggg 2220
atgagaaagc cagcattcct gtctggagag cagaagaaag ctatcgtgga cctcctcttc 2280
aagacgaacc ggaaagttac cgtgaaacag ctcaaagaag actatttcaa aaagattgaa 2340
tgtttcgact ctgttgaaat cagcggagtg gaggatcgct tcaacgcatc cctgggaacg 2400
tatcacgatc tcctgaaaat cattaaagac aaggacttcc tggacaatga ggagaacgag 2460
gacattcttg aggacattgt cctcaccctt acgttgtttg aagataggga gatgattgaa 2520
gaacgcttga aaacttacgc tcatctcttc gacgacaaag tcatgaaaca gctcaagagg 2580
cgccgatata caggatgggg gcggctgtca agaaaactga tcaatgggat ccgagacaag 2640
cagagtggaa agacaatcct ggattttctt aagtccgatg gatttgccaa ccggaacttc 2700
atgcagttga tccatgatga ctctctcacc tttaaggagg acatccagaa agcacaagtt 2760
tctggccagg gggacagtct tcacgagcac atcgctaatc ttgcaggtag cccagctatc 2820
aaaaagggaa tactgcagac cgttaaggtc gtggatgaac tcgtcaaagt aatgggaagg 2880
cataagcccg agaatatcgt tatcgagatg gcccgagaga accaaactac ccagaaggga 2940
cagaagaaca gtagggaaag gatgaagagg attgaagagg gtataaaaga actggggtcc 3000
caaatcctta aggaacaccc agttgaaaac acccagcttc agaatgagaa gctctacctg 3060
tactacctgc agaacggcag ggacatgtac gtggatcagg aactggacat caatcggctc 3120
tccgactacg acgtggatca tatcgtgccc cagtcttttc tcaaagatga ttctattgat 3180
aataaagtgt tgacaagatc cgataaaaat agagggaaga gtgataacgt cccctcagaa 3240
gaagttgtca agaaaatgaa aaattattgg cggcagctgc tgaacgccaa actgatcaca 3300
caacggaagt tcgataatct gactaaggct gaacgaggtg gcctgtctga gttggataaa 3360
gcaggcttca tcaaaaggca gcttgttgag acacgccaga tcaccaagca cgtggcccaa 3420
attctcgatt cacgcatgaa caccaagtac gatgaaaatg acaaactgat tcgagaggtg 3480
aaagttatta ctctgaagtc taagctggtc tcagatttca gaaaggactt tcagttttat 3540
aaggtgagag agatcaacaa ttaccaccat gcgcatgatg cctacctgaa tgcagtggta 3600
ggcactgcac ttatcaaaaa atatcccaag cttgaatctg aatttgttta cggagactat 3660
aaagtgtacg atgttaggaa aatgatcgca aagtctgagc aggaaatagg caaggccacc 3720
gctaagtact tcttttacag caatattatg aattttttca agaccgagat tacactggcc 3780
aatggagaga ttcggaagcg accacttatc gaaacaaacg gagaaacagg agaaatcgtg 3840
tgggacaagg gtagggattt cgcgacagtc cggaaggtcc tgtccatgcc gcaggtgaac 3900
atcgttaaaa agaccgaagt acagaccgga ggcttctcca aggaaagtat cctcccgaaa 3960
aggaacagcg acaagctgat cgcacgcaaa aaagattggg accccaagaa atacggcgga 4020
ttcgattctc ctacagtcgc ttacagtgta ctggttgtgg ccaaagtgga gaaagggaag 4080
tctaaaaaac tcaaaagcgt caaggaactg ctgggcatca caatcatgga gcgatcaagc 4140
ttcgaaaaaa accccatcga ctttctcgag gcgaaaggat ataaagaggt caaaaaagac 4200
ctcatcatta agcttcccaa gtactctctc tttgagcttg aaaacggccg gaaacgaatg 4260
ctcgctagtg cgggcgagct gcagaaaggt aacgagctgg cactgccctc taaatacgtt 4320
aatttcttgt atctggccag ccactatgaa aagctcaaag ggtctcccga agataatgag 4380
cagaagcagc tgttcgtgga acaacacaaa cactaccttg atgagatcat cgagcaaata 4440
agcgaattct ccaaaagagt gatcctcgcc gacgctaacc tcgataaggt gctttctgct 4500
tacaataagc acagggataa gcccatcagg gagcaggcag aaaacattat ccacttgttt 4560
actctgacca acttgggcgc gcctgcagcc ttcaagtact tcgacaccac catagacaga 4620
aagcggtaca cctctacaaa ggaggtcctg gacgccacac tgattcatca gtcaattacg 4680
gggctctatg aaacaagaat cgacctctct cagctcggtg gagac 4725
<210> 2
<211> 1575
<212> PRT
<213> b
<400> 2
Met Gly Ser Ser His His His His His His Ser Glu Val Glu Phe Ser
1 5 10 15
His Glu Tyr Trp Met Arg His Ala Leu Thr Leu Ala Lys Arg Ala Arg
20 25 30
Asp Glu Arg Glu Val Pro Val Gly Ala Val Leu Val Leu Asn Asn Arg
35 40 45
Val Ile Gly Glu Gly Trp Asn Arg Ala Ile Gly Leu His Asp Pro Thr
50 55 60
Ala His Ala Glu Ile Met Ala Leu Arg Gln Gly Gly Leu Val Met Gln
65 70 75 80
Asn Tyr Arg Leu Ile Asp Ala Thr Leu Tyr Val Thr Phe Glu Pro Cys
85 90 95
Val Met Cys Ala Gly Ala Met Ile His Ser Arg Ile Gly Arg Val Val
100 105 110
Phe Gly Val Arg Asn Ser Lys Arg Gly Ala Ala Gly Ser Leu Met Asn
115 120 125
Val Leu Asn Tyr Pro Gly Met Asn His Arg Val Glu Ile Thr Glu Gly
130 135 140
Ile Leu Ala Asp Glu Cys Ala Ala Leu Leu Cys Asp Phe Tyr Arg Met
145 150 155 160
Pro Arg Gln Val Phe Asn Ala Gln Lys Lys Ala Gln Ser Ser Ile Asn
165 170 175
Ser Gly Gly Ser Ser Gly Gly Ser Ser Gly Ser Glu Thr Pro Gly Thr
180 185 190
Ser Glu Ser Ala Thr Pro Glu Ser Ser Gly Gly Ser Ser Gly Gly Ser
195 200 205
Asp Lys Lys Tyr Ser Ile Gly Leu Ala Ile Gly Thr Asn Ser Val Gly
210 215 220
Trp Ala Val Ile Thr Asp Glu Tyr Lys Val Pro Ser Lys Lys Phe Lys
225 230 235 240
Val Leu Gly Asn Thr Asp Arg His Ser Ile Lys Lys Asn Leu Ile Gly
245 250 255
Ala Leu Leu Phe Asp Ser Gly Glu Thr Ala Glu Ala Thr Arg Leu Lys
260 265 270
Arg Thr Ala Arg Arg Arg Tyr Thr Arg Arg Lys Asn Arg Ile Cys Tyr
275 280 285
Leu Gln Glu Ile Phe Ser Asn Glu Met Ala Lys Val Asp Asp Ser Phe
290 295 300
Phe His Arg Leu Glu Glu Ser Phe Leu Val Glu Glu Asp Lys Lys His
305 310 315 320
Glu Arg His Pro Ile Phe Gly Asn Ile Val Asp Glu Val Ala Tyr His
325 330 335
Glu Lys Tyr Pro Thr Ile Tyr His Leu Arg Lys Lys Leu Val Asp Ser
340 345 350
Thr Asp Lys Ala Asp Leu Arg Leu Ile Tyr Leu Ala Leu Ala His Met
355 360 365
Ile Lys Phe Arg Gly His Phe Leu Ile Glu Gly Asp Leu Asn Pro Asp
370 375 380
Asn Ser Asp Val Asp Lys Leu Phe Ile Gln Leu Val Gln Thr Tyr Asn
385 390 395 400
Gln Leu Phe Glu Glu Asn Pro Ile Asn Ala Ser Gly Val Asp Ala Lys
405 410 415
Ala Ile Leu Ser Ala Arg Leu Ser Lys Ser Arg Arg Leu Glu Asn Leu
420 425 430
Ile Ala Gln Leu Pro Gly Glu Lys Lys Asn Gly Leu Phe Gly Asn Leu
435 440 445
Ile Ala Leu Ser Leu Gly Leu Thr Pro Asn Phe Lys Ser Asn Phe Asp
450 455 460
Leu Ala Glu Asp Ala Lys Leu Gln Leu Ser Lys Asp Thr Tyr Asp Asp
465 470 475 480
Asp Leu Asp Asn Leu Leu Ala Gln Ile Gly Asp Gln Tyr Ala Asp Leu
485 490 495
Phe Leu Ala Ala Lys Asn Leu Ser Asp Ala Ile Leu Leu Ser Asp Ile
500 505 510
Leu Arg Val Asn Thr Glu Ile Thr Lys Ala Pro Leu Ser Ala Ser Met
515 520 525
Ile Lys Arg Tyr Asp Glu His His Gln Asp Leu Thr Leu Leu Lys Ala
530 535 540
Leu Val Arg Gln Gln Leu Pro Glu Lys Tyr Lys Glu Ile Phe Phe Asp
545 550 555 560
Gln Ser Lys Asn Gly Tyr Ala Gly Tyr Ile Asp Gly Gly Ala Ser Gln
565 570 575
Glu Glu Phe Tyr Lys Phe Ile Lys Pro Ile Leu Glu Lys Met Asp Gly
580 585 590
Thr Glu Glu Leu Leu Val Lys Leu Asn Arg Glu Asp Leu Leu Arg Lys
595 600 605
Gln Arg Thr Phe Asp Asn Gly Ser Ile Pro His Gln Ile His Leu Gly
610 615 620
Glu Leu His Ala Ile Leu Arg Arg Gln Glu Asp Phe Tyr Pro Phe Leu
625 630 635 640
Lys Asp Asn Arg Glu Lys Ile Glu Lys Ile Leu Thr Phe Arg Ile Pro
645 650 655
Tyr Tyr Val Gly Pro Leu Ala Arg Gly Asn Ser Arg Phe Ala Trp Met
660 665 670
Thr Arg Lys Ser Glu Glu Thr Ile Thr Pro Trp Asn Phe Glu Glu Val
675 680 685
Val Asp Lys Gly Ala Ser Ala Gln Ser Phe Ile Glu Arg Met Thr Asn
690 695 700
Phe Asp Lys Asn Leu Pro Asn Glu Lys Val Leu Pro Lys His Ser Leu
705 710 715 720
Leu Tyr Glu Tyr Phe Thr Val Tyr Asn Glu Leu Thr Lys Val Lys Tyr
725 730 735
Val Thr Glu Gly Met Arg Lys Pro Ala Phe Leu Ser Gly Glu Gln Lys
740 745 750
Lys Ala Ile Val Asp Leu Leu Phe Lys Thr Asn Arg Lys Val Thr Val
755 760 765
Lys Gln Leu Lys Glu Asp Tyr Phe Lys Lys Ile Glu Cys Phe Asp Ser
770 775 780
Val Glu Ile Ser Gly Val Glu Asp Arg Phe Asn Ala Ser Leu Gly Thr
785 790 795 800
Tyr His Asp Leu Leu Lys Ile Ile Lys Asp Lys Asp Phe Leu Asp Asn
805 810 815
Glu Glu Asn Glu Asp Ile Leu Glu Asp Ile Val Leu Thr Leu Thr Leu
820 825 830
Phe Glu Asp Arg Glu Met Ile Glu Glu Arg Leu Lys Thr Tyr Ala His
835 840 845
Leu Phe Asp Asp Lys Val Met Lys Gln Leu Lys Arg Arg Arg Tyr Thr
850 855 860
Gly Trp Gly Arg Leu Ser Arg Lys Leu Ile Asn Gly Ile Arg Asp Lys
865 870 875 880
Gln Ser Gly Lys Thr Ile Leu Asp Phe Leu Lys Ser Asp Gly Phe Ala
885 890 895
Asn Arg Asn Phe Met Gln Leu Ile His Asp Asp Ser Leu Thr Phe Lys
900 905 910
Glu Asp Ile Gln Lys Ala Gln Val Ser Gly Gln Gly Asp Ser Leu His
915 920 925
Glu His Ile Ala Asn Leu Ala Gly Ser Pro Ala Ile Lys Lys Gly Ile
930 935 940
Leu Gln Thr Val Lys Val Val Asp Glu Leu Val Lys Val Met Gly Arg
945 950 955 960
His Lys Pro Glu Asn Ile Val Ile Glu Met Ala Arg Glu Asn Gln Thr
965 970 975
Thr Gln Lys Gly Gln Lys Asn Ser Arg Glu Arg Met Lys Arg Ile Glu
980 985 990
Glu Gly Ile Lys Glu Leu Gly Ser Gln Ile Leu Lys Glu His Pro Val
995 1000 1005
Glu Asn Thr Gln Leu Gln Asn Glu Lys Leu Tyr Leu Tyr Tyr Leu Gln
1010 1015 1020
Asn Gly Arg Asp Met Tyr Val Asp Gln Glu Leu Asp Ile Asn Arg Leu
1025 1030 1035 1040
Ser Asp Tyr Asp Val Asp His Ile Val Pro Gln Ser Phe Leu Lys Asp
1045 1050 1055
Asp Ser Ile Asp Asn Lys Val Leu Thr Arg Ser Asp Lys Asn Arg Gly
1060 1065 1070
Lys Ser Asp Asn Val Pro Ser Glu Glu Val Val Lys Lys Met Lys Asn
1075 1080 1085
Tyr Trp Arg Gln Leu Leu Asn Ala Lys Leu Ile Thr Gln Arg Lys Phe
1090 1095 1100
Asp Asn Leu Thr Lys Ala Glu Arg Gly Gly Leu Ser Glu Leu Asp Lys
1105 1110 1115 1120
Ala Gly Phe Ile Lys Arg Gln Leu Val Glu Thr Arg Gln Ile Thr Lys
1125 1130 1135
His Val Ala Gln Ile Leu Asp Ser Arg Met Asn Thr Lys Tyr Asp Glu
1140 1145 1150
Asn Asp Lys Leu Ile Arg Glu Val Lys Val Ile Thr Leu Lys Ser Lys
1155 1160 1165
Leu Val Ser Asp Phe Arg Lys Asp Phe Gln Phe Tyr Lys Val Arg Glu
1170 1175 1180
Ile Asn Asn Tyr His His Ala His Asp Ala Tyr Leu Asn Ala Val Val
1185 1190 1195 1200
Gly Thr Ala Leu Ile Lys Lys Tyr Pro Lys Leu Glu Ser Glu Phe Val
1205 1210 1215
Tyr Gly Asp Tyr Lys Val Tyr Asp Val Arg Lys Met Ile Ala Lys Ser
1220 1225 1230
Glu Gln Glu Ile Gly Lys Ala Thr Ala Lys Tyr Phe Phe Tyr Ser Asn
1235 1240 1245
Ile Met Asn Phe Phe Lys Thr Glu Ile Thr Leu Ala Asn Gly Glu Ile
1250 1255 1260
Arg Lys Arg Pro Leu Ile Glu Thr Asn Gly Glu Thr Gly Glu Ile Val
1265 1270 1275 1280
Trp Asp Lys Gly Arg Asp Phe Ala Thr Val Arg Lys Val Leu Ser Met
1285 1290 1295
Pro Gln Val Asn Ile Val Lys Lys Thr Glu Val Gln Thr Gly Gly Phe
1300 1305 1310
Ser Lys Glu Ser Ile Leu Pro Lys Arg Asn Ser Asp Lys Leu Ile Ala
1315 1320 1325
Arg Lys Lys Asp Trp Asp Pro Lys Lys Tyr Gly Gly Phe Asp Ser Pro
1330 1335 1340
Thr Val Ala Tyr Ser Val Leu Val Val Ala Lys Val Glu Lys Gly Lys
1345 1350 1355 1360
Ser Lys Lys Leu Lys Ser Val Lys Glu Leu Leu Gly Ile Thr Ile Met
1365 1370 1375
Glu Arg Ser Ser Phe Glu Lys Asn Pro Ile Asp Phe Leu Glu Ala Lys
1380 1385 1390
Gly Tyr Lys Glu Val Lys Lys Asp Leu Ile Ile Lys Leu Pro Lys Tyr
1395 1400 1405
Ser Leu Phe Glu Leu Glu Asn Gly Arg Lys Arg Met Leu Ala Ser Ala
1410 1415 1420
Gly Glu Leu Gln Lys Gly Asn Glu Leu Ala Leu Pro Ser Lys Tyr Val
1425 1430 1435 1440
Asn Phe Leu Tyr Leu Ala Ser His Tyr Glu Lys Leu Lys Gly Ser Pro
1445 1450 1455
Glu Asp Asn Glu Gln Lys Gln Leu Phe Val Glu Gln His Lys His Tyr
1460 1465 1470
Leu Asp Glu Ile Ile Glu Gln Ile Ser Glu Phe Ser Lys Arg Val Ile
1475 1480 1485
Leu Ala Asp Ala Asn Leu Asp Lys Val Leu Ser Ala Tyr Asn Lys His
1490 1495 1500
Arg Asp Lys Pro Ile Arg Glu Gln Ala Glu Asn Ile Ile His Leu Phe
1505 1510 1515 1520
Thr Leu Thr Asn Leu Gly Ala Pro Ala Ala Phe Lys Tyr Phe Asp Thr
1525 1530 1535
Thr Ile Asp Arg Lys Arg Tyr Thr Ser Thr Lys Glu Val Leu Asp Ala
1540 1545 1550
Thr Leu Ile His Gln Ser Ile Thr Gly Leu Tyr Glu Thr Arg Ile Asp
1555 1560 1565
Leu Ser Gln Leu Gly Gly Asp
1570 1575
<210> 3
<211> 4641
<212> DNA
<213> c
<400> 3
atgggcagca gccatcatca tcatcatcac tcggaggtcg agttttcaca tgagtattgg 60
atgcgtcatg ccttgacgtt ggcgaaacgg gcgcgcgatg agcgtgaggt gcccgtggga 120
gcggtgttgg tactgaataa ccgggttata ggggaaggat ggaaccgggc tattgggtta 180
cacgacccaa cggcgcacgc cgagataatg gcactgcgcc aagggggctt agttatgcag 240
aattatcgcc ttatcgatgc tacactgtat gtaacctttg aaccctgcgt aatgtgtgcg 300
ggggctatga tccactcgag aatagggcgc gtggtattcg gcgtacgcaa cagcaaacgt 360
ggggctgcgg gctcgttgat gaacgttctg aactaccccg gaatgaatca cagagtagag 420
atcacggagg gaattttggc cgacgaatgt gcagctttac tgtgcgattt ttatcggatg 480
ccgcggcaag tcttcaacgc acagaagaag gctcaatctt ccattaacga aacccgcagc 540
gataagaaat actcaatagg cttagctatc ggcacaaaca gcgtcggctg ggccgtcatt 600
acggacgagt acaaggtgcc gagcaaaaaa ttcaaagttc tgggcaatac cgatcgccac 660
agcataaaga agaacctcat tggcgccctc ctgttcgact ccggggagac ggccgaagcc 720
acgcggctca aaagaacagc acggcgcaga tatacccgca gaaagaatcg gatctgctac 780
ctgcaggaga tctttagtaa tgagatggct aaggtggatg actctttctt ccataggctg 840
gaggagtcct ttttggtgga ggaggataaa aagcacgagc gccacccaat ctttggcaat 900
atcgtggacg aggtggcgta ccatgaaaag tacccaacca tatatcatct gaggaagaag 960
cttgtagaca gtactgataa ggctgacttg cggttgatct atctcgcgct ggcgcatatg 1020
atcaaatttc ggggacactt cctcatcgag ggggacctga acccagacaa cagcgatgtc 1080
gacaaactct ttatccaact ggttcagact tacaatcagc ttttcgaaga gaacccgatc 1140
aacgcatccg gagttgacgc caaagcaatc ctgagcgcta ggctgtccaa atcccggcgg 1200
ctcgaaaacc tcatcgcaca gctccctggg gagaagaaga acggcctgtt tggtaatctt 1260
atcgccctgt cactcgggct gacccccaac tttaaatcta acttcgacct ggccgaagat 1320
gccaagcttc aactgagcaa agacacctac gatgatgatc tcgacaatct gctggcccag 1380
atcggcgacc agtacgcaga cctttttttg gcggcaaaga acctgtcaga cgccattctg 1440
ctgagtgata ttctgcgagt gaacacggag atcaccaaag ctccgctgag cgctagtatg 1500
atcaagcgct atgatgagca ccaccaagac ttgactttgc tgaaggccct tgtcagacag 1560
caactgcctg agaagtacaa ggaaattttc ttcgatcagt ctaaaaatgg ctacgccgga 1620
tacattgacg gcggagcaag ccaggaggaa ttttacaaat ttattaagcc catcttggaa 1680
aaaatggacg gcaccgagga gctgctggta aagcttaaca gagaagatct gttgcgcaaa 1740
cagcgcactt tcgacaatgg aagcatcccc caccagattc acctgggcga actgcacgct 1800
atcctcaggc ggcaagagga tttctacccc tttttgaaag ataacaggga aaagattgag 1860
aaaatcctca catttcggat accctactat gtaggccccc tcgcccgggg aaattccaga 1920
ttcgcgtgga tgactcgcaa atcagaagag accatcactc cctggaactt cgaggaagtc 1980
gtggataagg gggcctctgc ccagtccttc atcgaaagga tgactaactt tgataaaaat 2040
ctgcctaacg aaaaggtgct tcctaaacac tctctgctgt acgagtactt cacagtttat 2100
aacgagctca ccaaggtcaa atacgtcaca gaagggatga gaaagccagc attcctgtct 2160
ggagagcaga agaaagctat cgtggacctc ctcttcaaga cgaaccggaa agttaccgtg 2220
aaacagctca aagaagacta tttcaaaaag attgaatgtt tcgactctgt tgaaatcagc 2280
ggagtggagg atcgcttcaa cgcatccctg ggaacgtatc acgatctcct gaaaatcatt 2340
aaagacaagg acttcctgga caatgaggag aacgaggaca ttcttgagga cattgtcctc 2400
acccttacgt tgtttgaaga tagggagatg attgaagaac gcttgaaaac ttacgctcat 2460
ctcttcgacg acaaagtcat gaaacagctc aagaggcgcc gatatacagg atgggggcgg 2520
ctgtcaagaa aactgatcaa tgggatccga gacaagcaga gtggaaagac aatcctggat 2580
tttcttaagt ccgatggatt tgccaaccgg aacttcatgc agttgatcca tgatgactct 2640
ctcaccttta aggaggacat ccagaaagca caagtttctg gccaggggga cagtcttcac 2700
gagcacatcg ctaatcttgc aggtagccca gctatcaaaa agggaatact gcagaccgtt 2760
aaggtcgtgg atgaactcgt caaagtaatg ggaaggcata agcccgagaa tatcgttatc 2820
gagatggccc gagagaacca aactacccag aagggacaga agaacagtag ggaaaggatg 2880
aagaggattg aagagggtat aaaagaactg gggtcccaaa tccttaagga acacccagtt 2940
gaaaacaccc agcttcagaa tgagaagctc tacctgtact acctgcagaa cggcagggac 3000
atgtacgtgg atcaggaact ggacatcaat cggctctccg actacgacgt ggatcatatc 3060
gtgccccagt cttttctcaa agatgattct attgataata aagtgttgac aagatccgat 3120
aaaaatagag ggaagagtga taacgtcccc tcagaagaag ttgtcaagaa aatgaaaaat 3180
tattggcggc agctgctgaa cgccaaactg atcacacaac ggaagttcga taatctgact 3240
aaggctgaac gaggtggcct gtctgagttg gataaagcag gcttcatcaa aaggcagctt 3300
gttgagacac gccagatcac caagcacgtg gcccaaattc tcgattcacg catgaacacc 3360
aagtacgatg aaaatgacaa actgattcga gaggtgaaag ttattactct gaagtctaag 3420
ctggtctcag atttcagaaa ggactttcag ttttataagg tgagagagat caacaattac 3480
caccatgcgc atgatgccta cctgaatgca gtggtaggca ctgcacttat caaaaaatat 3540
cccaagcttg aatctgaatt tgtttacgga gactataaag tgtacgatgt taggaaaatg 3600
atcgcaaagt ctgagcagga aataggcaag gccaccgcta agtacttctt ttacagcaat 3660
attatgaatt ttttcaagac cgagattaca ctggccaatg gagagattcg gaagcgacca 3720
cttatcgaaa caaacggaga aacaggagaa atcgtgtggg acaagggtag ggatttcgcg 3780
acagtccgga aggtcctgtc catgccgcag gtgaacatcg ttaaaaagac cgaagtacag 3840
accggaggct tctccaagga aagtatcctc ccgaaaagga acagcgacaa gctgatcgca 3900
cgcaaaaaag attgggaccc caagaaatac ggcggattcg attctcctac agtcgcttac 3960
agtgtactgg ttgtggccaa agtggagaaa gggaagtcta aaaaactcaa aagcgtcaag 4020
gaactgctgg gcatcacaat catggagcga tcaagcttcg aaaaaaaccc catcgacttt 4080
ctcgaggcga aaggatataa agaggtcaaa aaagacctca tcattaagct tcccaagtac 4140
tctctctttg agcttgaaaa cggccggaaa cgaatgctcg ctagtgcggg cgagctgcag 4200
aaaggtaacg agctggcact gccctctaaa tacgttaatt tcttgtatct ggccagccac 4260
tatgaaaagc tcaaagggtc tcccgaagat aatgagcaga agcagctgtt cgtggaacaa 4320
cacaaacact accttgatga gatcatcgag caaataagcg aattctccaa aagagtgatc 4380
ctcgccgacg ctaacctcga taaggtgctt tctgcttaca ataagcacag ggataagccc 4440
atcagggagc aggcagaaaa cattatccac ttgtttactc tgaccaactt gggcgcgcct 4500
gcagccttca agtacttcga caccaccata gacagaaagc ggtacacctc tacaaaggag 4560
gtcctggacg ccacactgat tcatcagtca attacggggc tctatgaaac aagaatcgac 4620
ctctctcagc tcggtggaga c 4641
<210> 4
<211> 1547
<212> PRT
<213> d
<400> 4
Met Gly Ser Ser His His His His His His Ser Glu Val Glu Phe Ser
1 5 10 15
His Glu Tyr Trp Met Arg His Ala Leu Thr Leu Ala Lys Arg Ala Arg
20 25 30
Asp Glu Arg Glu Val Pro Val Gly Ala Val Leu Val Leu Asn Asn Arg
35 40 45
Val Ile Gly Glu Gly Trp Asn Arg Ala Ile Gly Leu His Asp Pro Thr
50 55 60
Ala His Ala Glu Ile Met Ala Leu Arg Gln Gly Gly Leu Val Met Gln
65 70 75 80
Asn Tyr Arg Leu Ile Asp Ala Thr Leu Tyr Val Thr Phe Glu Pro Cys
85 90 95
Val Met Cys Ala Gly Ala Met Ile His Ser Arg Ile Gly Arg Val Val
100 105 110
Phe Gly Val Arg Asn Ser Lys Arg Gly Ala Ala Gly Ser Leu Met Asn
115 120 125
Val Leu Asn Tyr Pro Gly Met Asn His Arg Val Glu Ile Thr Glu Gly
130 135 140
Ile Leu Ala Asp Glu Cys Ala Ala Leu Leu Cys Asp Phe Tyr Arg Met
145 150 155 160
Pro Arg Gln Val Phe Asn Ala Gln Lys Lys Ala Gln Ser Ser Ile Asn
165 170 175
Glu Thr Arg Ser Asp Lys Lys Tyr Ser Ile Gly Leu Ala Ile Gly Thr
180 185 190
Asn Ser Val Gly Trp Ala Val Ile Thr Asp Glu Tyr Lys Val Pro Ser
195 200 205
Lys Lys Phe Lys Val Leu Gly Asn Thr Asp Arg His Ser Ile Lys Lys
210 215 220
Asn Leu Ile Gly Ala Leu Leu Phe Asp Ser Gly Glu Thr Ala Glu Ala
225 230 235 240
Thr Arg Leu Lys Arg Thr Ala Arg Arg Arg Tyr Thr Arg Arg Lys Asn
245 250 255
Arg Ile Cys Tyr Leu Gln Glu Ile Phe Ser Asn Glu Met Ala Lys Val
260 265 270
Asp Asp Ser Phe Phe His Arg Leu Glu Glu Ser Phe Leu Val Glu Glu
275 280 285
Asp Lys Lys His Glu Arg His Pro Ile Phe Gly Asn Ile Val Asp Glu
290 295 300
Val Ala Tyr His Glu Lys Tyr Pro Thr Ile Tyr His Leu Arg Lys Lys
305 310 315 320
Leu Val Asp Ser Thr Asp Lys Ala Asp Leu Arg Leu Ile Tyr Leu Ala
325 330 335
Leu Ala His Met Ile Lys Phe Arg Gly His Phe Leu Ile Glu Gly Asp
340 345 350
Leu Asn Pro Asp Asn Ser Asp Val Asp Lys Leu Phe Ile Gln Leu Val
355 360 365
Gln Thr Tyr Asn Gln Leu Phe Glu Glu Asn Pro Ile Asn Ala Ser Gly
370 375 380
Val Asp Ala Lys Ala Ile Leu Ser Ala Arg Leu Ser Lys Ser Arg Arg
385 390 395 400
Leu Glu Asn Leu Ile Ala Gln Leu Pro Gly Glu Lys Lys Asn Gly Leu
405 410 415
Phe Gly Asn Leu Ile Ala Leu Ser Leu Gly Leu Thr Pro Asn Phe Lys
420 425 430
Ser Asn Phe Asp Leu Ala Glu Asp Ala Lys Leu Gln Leu Ser Lys Asp
435 440 445
Thr Tyr Asp Asp Asp Leu Asp Asn Leu Leu Ala Gln Ile Gly Asp Gln
450 455 460
Tyr Ala Asp Leu Phe Leu Ala Ala Lys Asn Leu Ser Asp Ala Ile Leu
465 470 475 480
Leu Ser Asp Ile Leu Arg Val Asn Thr Glu Ile Thr Lys Ala Pro Leu
485 490 495
Ser Ala Ser Met Ile Lys Arg Tyr Asp Glu His His Gln Asp Leu Thr
500 505 510
Leu Leu Lys Ala Leu Val Arg Gln Gln Leu Pro Glu Lys Tyr Lys Glu
515 520 525
Ile Phe Phe Asp Gln Ser Lys Asn Gly Tyr Ala Gly Tyr Ile Asp Gly
530 535 540
Gly Ala Ser Gln Glu Glu Phe Tyr Lys Phe Ile Lys Pro Ile Leu Glu
545 550 555 560
Lys Met Asp Gly Thr Glu Glu Leu Leu Val Lys Leu Asn Arg Glu Asp
565 570 575
Leu Leu Arg Lys Gln Arg Thr Phe Asp Asn Gly Ser Ile Pro His Gln
580 585 590
Ile His Leu Gly Glu Leu His Ala Ile Leu Arg Arg Gln Glu Asp Phe
595 600 605
Tyr Pro Phe Leu Lys Asp Asn Arg Glu Lys Ile Glu Lys Ile Leu Thr
610 615 620
Phe Arg Ile Pro Tyr Tyr Val Gly Pro Leu Ala Arg Gly Asn Ser Arg
625 630 635 640
Phe Ala Trp Met Thr Arg Lys Ser Glu Glu Thr Ile Thr Pro Trp Asn
645 650 655
Phe Glu Glu Val Val Asp Lys Gly Ala Ser Ala Gln Ser Phe Ile Glu
660 665 670
Arg Met Thr Asn Phe Asp Lys Asn Leu Pro Asn Glu Lys Val Leu Pro
675 680 685
Lys His Ser Leu Leu Tyr Glu Tyr Phe Thr Val Tyr Asn Glu Leu Thr
690 695 700
Lys Val Lys Tyr Val Thr Glu Gly Met Arg Lys Pro Ala Phe Leu Ser
705 710 715 720
Gly Glu Gln Lys Lys Ala Ile Val Asp Leu Leu Phe Lys Thr Asn Arg
725 730 735
Lys Val Thr Val Lys Gln Leu Lys Glu Asp Tyr Phe Lys Lys Ile Glu
740 745 750
Cys Phe Asp Ser Val Glu Ile Ser Gly Val Glu Asp Arg Phe Asn Ala
755 760 765
Ser Leu Gly Thr Tyr His Asp Leu Leu Lys Ile Ile Lys Asp Lys Asp
770 775 780
Phe Leu Asp Asn Glu Glu Asn Glu Asp Ile Leu Glu Asp Ile Val Leu
785 790 795 800
Thr Leu Thr Leu Phe Glu Asp Arg Glu Met Ile Glu Glu Arg Leu Lys
805 810 815
Thr Tyr Ala His Leu Phe Asp Asp Lys Val Met Lys Gln Leu Lys Arg
820 825 830
Arg Arg Tyr Thr Gly Trp Gly Arg Leu Ser Arg Lys Leu Ile Asn Gly
835 840 845
Ile Arg Asp Lys Gln Ser Gly Lys Thr Ile Leu Asp Phe Leu Lys Ser
850 855 860
Asp Gly Phe Ala Asn Arg Asn Phe Met Gln Leu Ile His Asp Asp Ser
865 870 875 880
Leu Thr Phe Lys Glu Asp Ile Gln Lys Ala Gln Val Ser Gly Gln Gly
885 890 895
Asp Ser Leu His Glu His Ile Ala Asn Leu Ala Gly Ser Pro Ala Ile
900 905 910
Lys Lys Gly Ile Leu Gln Thr Val Lys Val Val Asp Glu Leu Val Lys
915 920 925
Val Met Gly Arg His Lys Pro Glu Asn Ile Val Ile Glu Met Ala Arg
930 935 940
Glu Asn Gln Thr Thr Gln Lys Gly Gln Lys Asn Ser Arg Glu Arg Met
945 950 955 960
Lys Arg Ile Glu Glu Gly Ile Lys Glu Leu Gly Ser Gln Ile Leu Lys
965 970 975
Glu His Pro Val Glu Asn Thr Gln Leu Gln Asn Glu Lys Leu Tyr Leu
980 985 990
Tyr Tyr Leu Gln Asn Gly Arg Asp Met Tyr Val Asp Gln Glu Leu Asp
995 1000 1005
Ile Asn Arg Leu Ser Asp Tyr Asp Val Asp His Ile Val Pro Gln Ser
1010 1015 1020
Phe Leu Lys Asp Asp Ser Ile Asp Asn Lys Val Leu Thr Arg Ser Asp
1025 1030 1035 1040
Lys Asn Arg Gly Lys Ser Asp Asn Val Pro Ser Glu Glu Val Val Lys
1045 1050 1055
Lys Met Lys Asn Tyr Trp Arg Gln Leu Leu Asn Ala Lys Leu Ile Thr
1060 1065 1070
Gln Arg Lys Phe Asp Asn Leu Thr Lys Ala Glu Arg Gly Gly Leu Ser
1075 1080 1085
Glu Leu Asp Lys Ala Gly Phe Ile Lys Arg Gln Leu Val Glu Thr Arg
1090 1095 1100
Gln Ile Thr Lys His Val Ala Gln Ile Leu Asp Ser Arg Met Asn Thr
1105 1110 1115 1120
Lys Tyr Asp Glu Asn Asp Lys Leu Ile Arg Glu Val Lys Val Ile Thr
1125 1130 1135
Leu Lys Ser Lys Leu Val Ser Asp Phe Arg Lys Asp Phe Gln Phe Tyr
1140 1145 1150
Lys Val Arg Glu Ile Asn Asn Tyr His His Ala His Asp Ala Tyr Leu
1155 1160 1165
Asn Ala Val Val Gly Thr Ala Leu Ile Lys Lys Tyr Pro Lys Leu Glu
1170 1175 1180
Ser Glu Phe Val Tyr Gly Asp Tyr Lys Val Tyr Asp Val Arg Lys Met
1185 1190 1195 1200
Ile Ala Lys Ser Glu Gln Glu Ile Gly Lys Ala Thr Ala Lys Tyr Phe
1205 1210 1215
Phe Tyr Ser Asn Ile Met Asn Phe Phe Lys Thr Glu Ile Thr Leu Ala
1220 1225 1230
Asn Gly Glu Ile Arg Lys Arg Pro Leu Ile Glu Thr Asn Gly Glu Thr
1235 1240 1245
Gly Glu Ile Val Trp Asp Lys Gly Arg Asp Phe Ala Thr Val Arg Lys
1250 1255 1260
Val Leu Ser Met Pro Gln Val Asn Ile Val Lys Lys Thr Glu Val Gln
1265 1270 1275 1280
Thr Gly Gly Phe Ser Lys Glu Ser Ile Leu Pro Lys Arg Asn Ser Asp
1285 1290 1295
Lys Leu Ile Ala Arg Lys Lys Asp Trp Asp Pro Lys Lys Tyr Gly Gly
1300 1305 1310
Phe Asp Ser Pro Thr Val Ala Tyr Ser Val Leu Val Val Ala Lys Val
1315 1320 1325
Glu Lys Gly Lys Ser Lys Lys Leu Lys Ser Val Lys Glu Leu Leu Gly
1330 1335 1340
Ile Thr Ile Met Glu Arg Ser Ser Phe Glu Lys Asn Pro Ile Asp Phe
1345 1350 1355 1360
Leu Glu Ala Lys Gly Tyr Lys Glu Val Lys Lys Asp Leu Ile Ile Lys
1365 1370 1375
Leu Pro Lys Tyr Ser Leu Phe Glu Leu Glu Asn Gly Arg Lys Arg Met
1380 1385 1390
Leu Ala Ser Ala Gly Glu Leu Gln Lys Gly Asn Glu Leu Ala Leu Pro
1395 1400 1405
Ser Lys Tyr Val Asn Phe Leu Tyr Leu Ala Ser His Tyr Glu Lys Leu
1410 1415 1420
Lys Gly Ser Pro Glu Asp Asn Glu Gln Lys Gln Leu Phe Val Glu Gln
1425 1430 1435 1440
His Lys His Tyr Leu Asp Glu Ile Ile Glu Gln Ile Ser Glu Phe Ser
1445 1450 1455
Lys Arg Val Ile Leu Ala Asp Ala Asn Leu Asp Lys Val Leu Ser Ala
1460 1465 1470
Tyr Asn Lys His Arg Asp Lys Pro Ile Arg Glu Gln Ala Glu Asn Ile
1475 1480 1485
Ile His Leu Phe Thr Leu Thr Asn Leu Gly Ala Pro Ala Ala Phe Lys
1490 1495 1500
Tyr Phe Asp Thr Thr Ile Asp Arg Lys Arg Tyr Thr Ser Thr Lys Glu
1505 1510 1515 1520
Val Leu Asp Ala Thr Leu Ile His Gln Ser Ile Thr Gly Leu Tyr Glu
1525 1530 1535
Thr Arg Ile Asp Leu Ser Gln Leu Gly Gly Asp
1540 1545
<210> 5
<211> 4641
<212> DNA
<213> e
<400> 5
atgggcagca gccatcatca tcatcatcac tcggaggtcg agttttcaca tgagtattgg 60
atgcgtcatg ccttgacgtt ggcgaaacgg gcgcgcgatg agcgtgaggt gcccgtggga 120
gcggtgttgg tactgaataa ccgggttata ggggaaggat ggaaccgggc tattgggtta 180
cacgacccaa cggcgcacgc cgagataatg gcactgcgcc aagggggctt agttatgcag 240
aattatcgcc ttatcgatgc tacactgtat gtaacctttg aaccctgcgt aatgtgtgcg 300
ggggctatga tccactcgag aatagggcgc gtggtattcg gcgtacgcaa cagcaaacgt 360
ggggctgcgg gctcgttgat gaacgttctg aactaccccg gaatgaatca cagagtagag 420
atcacggagg gaattttggc cgacgaatgt gcagctttac tgtgcgattt ttatcggatg 480
ccgcggcaag tcttcaacgc acagaagaag gctcaatctt ccattaaccc ggcgccggcg 540
gataagaaat actcaatagg cttagctatc ggcacaaaca gcgtcggctg ggccgtcatt 600
acggacgagt acaaggtgcc gagcaaaaaa ttcaaagttc tgggcaatac cgatcgccac 660
agcataaaga agaacctcat tggcgccctc ctgttcgact ccggggagac ggccgaagcc 720
acgcggctca aaagaacagc acggcgcaga tatacccgca gaaagaatcg gatctgctac 780
ctgcaggaga tctttagtaa tgagatggct aaggtggatg actctttctt ccataggctg 840
gaggagtcct ttttggtgga ggaggataaa aagcacgagc gccacccaat ctttggcaat 900
atcgtggacg aggtggcgta ccatgaaaag tacccaacca tatatcatct gaggaagaag 960
cttgtagaca gtactgataa ggctgacttg cggttgatct atctcgcgct ggcgcatatg 1020
atcaaatttc ggggacactt cctcatcgag ggggacctga acccagacaa cagcgatgtc 1080
gacaaactct ttatccaact ggttcagact tacaatcagc ttttcgaaga gaacccgatc 1140
aacgcatccg gagttgacgc caaagcaatc ctgagcgcta ggctgtccaa atcccggcgg 1200
ctcgaaaacc tcatcgcaca gctccctggg gagaagaaga acggcctgtt tggtaatctt 1260
atcgccctgt cactcgggct gacccccaac tttaaatcta acttcgacct ggccgaagat 1320
gccaagcttc aactgagcaa agacacctac gatgatgatc tcgacaatct gctggcccag 1380
atcggcgacc agtacgcaga cctttttttg gcggcaaaga acctgtcaga cgccattctg 1440
ctgagtgata ttctgcgagt gaacacggag atcaccaaag ctccgctgag cgctagtatg 1500
atcaagcgct atgatgagca ccaccaagac ttgactttgc tgaaggccct tgtcagacag 1560
caactgcctg agaagtacaa ggaaattttc ttcgatcagt ctaaaaatgg ctacgccgga 1620
tacattgacg gcggagcaag ccaggaggaa ttttacaaat ttattaagcc catcttggaa 1680
aaaatggacg gcaccgagga gctgctggta aagcttaaca gagaagatct gttgcgcaaa 1740
cagcgcactt tcgacaatgg aagcatcccc caccagattc acctgggcga actgcacgct 1800
atcctcaggc ggcaagagga tttctacccc tttttgaaag ataacaggga aaagattgag 1860
aaaatcctca catttcggat accctactat gtaggccccc tcgcccgggg aaattccaga 1920
ttcgcgtgga tgactcgcaa atcagaagag accatcactc cctggaactt cgaggaagtc 1980
gtggataagg gggcctctgc ccagtccttc atcgaaagga tgactaactt tgataaaaat 2040
ctgcctaacg aaaaggtgct tcctaaacac tctctgctgt acgagtactt cacagtttat 2100
aacgagctca ccaaggtcaa atacgtcaca gaagggatga gaaagccagc attcctgtct 2160
ggagagcaga agaaagctat cgtggacctc ctcttcaaga cgaaccggaa agttaccgtg 2220
aaacagctca aagaagacta tttcaaaaag attgaatgtt tcgactctgt tgaaatcagc 2280
ggagtggagg atcgcttcaa cgcatccctg ggaacgtatc acgatctcct gaaaatcatt 2340
aaagacaagg acttcctgga caatgaggag aacgaggaca ttcttgagga cattgtcctc 2400
acccttacgt tgtttgaaga tagggagatg attgaagaac gcttgaaaac ttacgctcat 2460
ctcttcgacg acaaagtcat gaaacagctc aagaggcgcc gatatacagg atgggggcgg 2520
ctgtcaagaa aactgatcaa tgggatccga gacaagcaga gtggaaagac aatcctggat 2580
tttcttaagt ccgatggatt tgccaaccgg aacttcatgc agttgatcca tgatgactct 2640
ctcaccttta aggaggacat ccagaaagca caagtttctg gccaggggga cagtcttcac 2700
gagcacatcg ctaatcttgc aggtagccca gctatcaaaa agggaatact gcagaccgtt 2760
aaggtcgtgg atgaactcgt caaagtaatg ggaaggcata agcccgagaa tatcgttatc 2820
gagatggccc gagagaacca aactacccag aagggacaga agaacagtag ggaaaggatg 2880
aagaggattg aagagggtat aaaagaactg gggtcccaaa tccttaagga acacccagtt 2940
gaaaacaccc agcttcagaa tgagaagctc tacctgtact acctgcagaa cggcagggac 3000
atgtacgtgg atcaggaact ggacatcaat cggctctccg actacgacgt ggatcatatc 3060
gtgccccagt cttttctcaa agatgattct attgataata aagtgttgac aagatccgat 3120
aaaaatagag ggaagagtga taacgtcccc tcagaagaag ttgtcaagaa aatgaaaaat 3180
tattggcggc agctgctgaa cgccaaactg atcacacaac ggaagttcga taatctgact 3240
aaggctgaac gaggtggcct gtctgagttg gataaagcag gcttcatcaa aaggcagctt 3300
gttgagacac gccagatcac caagcacgtg gcccaaattc tcgattcacg catgaacacc 3360
aagtacgatg aaaatgacaa actgattcga gaggtgaaag ttattactct gaagtctaag 3420
ctggtctcag atttcagaaa ggactttcag ttttataagg tgagagagat caacaattac 3480
caccatgcgc atgatgccta cctgaatgca gtggtaggca ctgcacttat caaaaaatat 3540
cccaagcttg aatctgaatt tgtttacgga gactataaag tgtacgatgt taggaaaatg 3600
atcgcaaagt ctgagcagga aataggcaag gccaccgcta agtacttctt ttacagcaat 3660
attatgaatt ttttcaagac cgagattaca ctggccaatg gagagattcg gaagcgacca 3720
cttatcgaaa caaacggaga aacaggagaa atcgtgtggg acaagggtag ggatttcgcg 3780
acagtccgga aggtcctgtc catgccgcag gtgaacatcg ttaaaaagac cgaagtacag 3840
accggaggct tctccaagga aagtatcctc ccgaaaagga acagcgacaa gctgatcgca 3900
cgcaaaaaag attgggaccc caagaaatac ggcggattcg attctcctac agtcgcttac 3960
agtgtactgg ttgtggccaa agtggagaaa gggaagtcta aaaaactcaa aagcgtcaag 4020
gaactgctgg gcatcacaat catggagcga tcaagcttcg aaaaaaaccc catcgacttt 4080
ctcgaggcga aaggatataa agaggtcaaa aaagacctca tcattaagct tcccaagtac 4140
tctctctttg agcttgaaaa cggccggaaa cgaatgctcg ctagtgcggg cgagctgcag 4200
aaaggtaacg agctggcact gccctctaaa tacgttaatt tcttgtatct ggccagccac 4260
tatgaaaagc tcaaagggtc tcccgaagat aatgagcaga agcagctgtt cgtggaacaa 4320
cacaaacact accttgatga gatcatcgag caaataagcg aattctccaa aagagtgatc 4380
ctcgccgacg ctaacctcga taaggtgctt tctgcttaca ataagcacag ggataagccc 4440
atcagggagc aggcagaaaa cattatccac ttgtttactc tgaccaactt gggcgcgcct 4500
gcagccttca agtacttcga caccaccata gacagaaagc ggtacacctc tacaaaggag 4560
gtcctggacg ccacactgat tcatcagtca attacggggc tctatgaaac aagaatcgac 4620
ctctctcagc tcggtggaga c 4641
<210> 6
<211> 1547
<212> PRT
<213> f
<400> 6
Met Gly Ser Ser His His His His His His Ser Glu Val Glu Phe Ser
1 5 10 15
His Glu Tyr Trp Met Arg His Ala Leu Thr Leu Ala Lys Arg Ala Arg
20 25 30
Asp Glu Arg Glu Val Pro Val Gly Ala Val Leu Val Leu Asn Asn Arg
35 40 45
Val Ile Gly Glu Gly Trp Asn Arg Ala Ile Gly Leu His Asp Pro Thr
50 55 60
Ala His Ala Glu Ile Met Ala Leu Arg Gln Gly Gly Leu Val Met Gln
65 70 75 80
Asn Tyr Arg Leu Ile Asp Ala Thr Leu Tyr Val Thr Phe Glu Pro Cys
85 90 95
Val Met Cys Ala Gly Ala Met Ile His Ser Arg Ile Gly Arg Val Val
100 105 110
Phe Gly Val Arg Asn Ser Lys Arg Gly Ala Ala Gly Ser Leu Met Asn
115 120 125
Val Leu Asn Tyr Pro Gly Met Asn His Arg Val Glu Ile Thr Glu Gly
130 135 140
Ile Leu Ala Asp Glu Cys Ala Ala Leu Leu Cys Asp Phe Tyr Arg Met
145 150 155 160
Pro Arg Gln Val Phe Asn Ala Gln Lys Lys Ala Gln Ser Ser Ile Asn
165 170 175
Pro Ala Pro Ala Asp Lys Lys Tyr Ser Ile Gly Leu Ala Ile Gly Thr
180 185 190
Asn Ser Val Gly Trp Ala Val Ile Thr Asp Glu Tyr Lys Val Pro Ser
195 200 205
Lys Lys Phe Lys Val Leu Gly Asn Thr Asp Arg His Ser Ile Lys Lys
210 215 220
Asn Leu Ile Gly Ala Leu Leu Phe Asp Ser Gly Glu Thr Ala Glu Ala
225 230 235 240
Thr Arg Leu Lys Arg Thr Ala Arg Arg Arg Tyr Thr Arg Arg Lys Asn
245 250 255
Arg Ile Cys Tyr Leu Gln Glu Ile Phe Ser Asn Glu Met Ala Lys Val
260 265 270
Asp Asp Ser Phe Phe His Arg Leu Glu Glu Ser Phe Leu Val Glu Glu
275 280 285
Asp Lys Lys His Glu Arg His Pro Ile Phe Gly Asn Ile Val Asp Glu
290 295 300
Val Ala Tyr His Glu Lys Tyr Pro Thr Ile Tyr His Leu Arg Lys Lys
305 310 315 320
Leu Val Asp Ser Thr Asp Lys Ala Asp Leu Arg Leu Ile Tyr Leu Ala
325 330 335
Leu Ala His Met Ile Lys Phe Arg Gly His Phe Leu Ile Glu Gly Asp
340 345 350
Leu Asn Pro Asp Asn Ser Asp Val Asp Lys Leu Phe Ile Gln Leu Val
355 360 365
Gln Thr Tyr Asn Gln Leu Phe Glu Glu Asn Pro Ile Asn Ala Ser Gly
370 375 380
Val Asp Ala Lys Ala Ile Leu Ser Ala Arg Leu Ser Lys Ser Arg Arg
385 390 395 400
Leu Glu Asn Leu Ile Ala Gln Leu Pro Gly Glu Lys Lys Asn Gly Leu
405 410 415
Phe Gly Asn Leu Ile Ala Leu Ser Leu Gly Leu Thr Pro Asn Phe Lys
420 425 430
Ser Asn Phe Asp Leu Ala Glu Asp Ala Lys Leu Gln Leu Ser Lys Asp
435 440 445
Thr Tyr Asp Asp Asp Leu Asp Asn Leu Leu Ala Gln Ile Gly Asp Gln
450 455 460
Tyr Ala Asp Leu Phe Leu Ala Ala Lys Asn Leu Ser Asp Ala Ile Leu
465 470 475 480
Leu Ser Asp Ile Leu Arg Val Asn Thr Glu Ile Thr Lys Ala Pro Leu
485 490 495
Ser Ala Ser Met Ile Lys Arg Tyr Asp Glu His His Gln Asp Leu Thr
500 505 510
Leu Leu Lys Ala Leu Val Arg Gln Gln Leu Pro Glu Lys Tyr Lys Glu
515 520 525
Ile Phe Phe Asp Gln Ser Lys Asn Gly Tyr Ala Gly Tyr Ile Asp Gly
530 535 540
Gly Ala Ser Gln Glu Glu Phe Tyr Lys Phe Ile Lys Pro Ile Leu Glu
545 550 555 560
Lys Met Asp Gly Thr Glu Glu Leu Leu Val Lys Leu Asn Arg Glu Asp
565 570 575
Leu Leu Arg Lys Gln Arg Thr Phe Asp Asn Gly Ser Ile Pro His Gln
580 585 590
Ile His Leu Gly Glu Leu His Ala Ile Leu Arg Arg Gln Glu Asp Phe
595 600 605
Tyr Pro Phe Leu Lys Asp Asn Arg Glu Lys Ile Glu Lys Ile Leu Thr
610 615 620
Phe Arg Ile Pro Tyr Tyr Val Gly Pro Leu Ala Arg Gly Asn Ser Arg
625 630 635 640
Phe Ala Trp Met Thr Arg Lys Ser Glu Glu Thr Ile Thr Pro Trp Asn
645 650 655
Phe Glu Glu Val Val Asp Lys Gly Ala Ser Ala Gln Ser Phe Ile Glu
660 665 670
Arg Met Thr Asn Phe Asp Lys Asn Leu Pro Asn Glu Lys Val Leu Pro
675 680 685
Lys His Ser Leu Leu Tyr Glu Tyr Phe Thr Val Tyr Asn Glu Leu Thr
690 695 700
Lys Val Lys Tyr Val Thr Glu Gly Met Arg Lys Pro Ala Phe Leu Ser
705 710 715 720
Gly Glu Gln Lys Lys Ala Ile Val Asp Leu Leu Phe Lys Thr Asn Arg
725 730 735
Lys Val Thr Val Lys Gln Leu Lys Glu Asp Tyr Phe Lys Lys Ile Glu
740 745 750
Cys Phe Asp Ser Val Glu Ile Ser Gly Val Glu Asp Arg Phe Asn Ala
755 760 765
Ser Leu Gly Thr Tyr His Asp Leu Leu Lys Ile Ile Lys Asp Lys Asp
770 775 780
Phe Leu Asp Asn Glu Glu Asn Glu Asp Ile Leu Glu Asp Ile Val Leu
785 790 795 800
Thr Leu Thr Leu Phe Glu Asp Arg Glu Met Ile Glu Glu Arg Leu Lys
805 810 815
Thr Tyr Ala His Leu Phe Asp Asp Lys Val Met Lys Gln Leu Lys Arg
820 825 830
Arg Arg Tyr Thr Gly Trp Gly Arg Leu Ser Arg Lys Leu Ile Asn Gly
835 840 845
Ile Arg Asp Lys Gln Ser Gly Lys Thr Ile Leu Asp Phe Leu Lys Ser
850 855 860
Asp Gly Phe Ala Asn Arg Asn Phe Met Gln Leu Ile His Asp Asp Ser
865 870 875 880
Leu Thr Phe Lys Glu Asp Ile Gln Lys Ala Gln Val Ser Gly Gln Gly
885 890 895
Asp Ser Leu His Glu His Ile Ala Asn Leu Ala Gly Ser Pro Ala Ile
900 905 910
Lys Lys Gly Ile Leu Gln Thr Val Lys Val Val Asp Glu Leu Val Lys
915 920 925
Val Met Gly Arg His Lys Pro Glu Asn Ile Val Ile Glu Met Ala Arg
930 935 940
Glu Asn Gln Thr Thr Gln Lys Gly Gln Lys Asn Ser Arg Glu Arg Met
945 950 955 960
Lys Arg Ile Glu Glu Gly Ile Lys Glu Leu Gly Ser Gln Ile Leu Lys
965 970 975
Glu His Pro Val Glu Asn Thr Gln Leu Gln Asn Glu Lys Leu Tyr Leu
980 985 990
Tyr Tyr Leu Gln Asn Gly Arg Asp Met Tyr Val Asp Gln Glu Leu Asp
995 1000 1005
Ile Asn Arg Leu Ser Asp Tyr Asp Val Asp His Ile Val Pro Gln Ser
1010 1015 1020
Phe Leu Lys Asp Asp Ser Ile Asp Asn Lys Val Leu Thr Arg Ser Asp
1025 1030 1035 1040
Lys Asn Arg Gly Lys Ser Asp Asn Val Pro Ser Glu Glu Val Val Lys
1045 1050 1055
Lys Met Lys Asn Tyr Trp Arg Gln Leu Leu Asn Ala Lys Leu Ile Thr
1060 1065 1070
Gln Arg Lys Phe Asp Asn Leu Thr Lys Ala Glu Arg Gly Gly Leu Ser
1075 1080 1085
Glu Leu Asp Lys Ala Gly Phe Ile Lys Arg Gln Leu Val Glu Thr Arg
1090 1095 1100
Gln Ile Thr Lys His Val Ala Gln Ile Leu Asp Ser Arg Met Asn Thr
1105 1110 1115 1120
Lys Tyr Asp Glu Asn Asp Lys Leu Ile Arg Glu Val Lys Val Ile Thr
1125 1130 1135
Leu Lys Ser Lys Leu Val Ser Asp Phe Arg Lys Asp Phe Gln Phe Tyr
1140 1145 1150
Lys Val Arg Glu Ile Asn Asn Tyr His His Ala His Asp Ala Tyr Leu
1155 1160 1165
Asn Ala Val Val Gly Thr Ala Leu Ile Lys Lys Tyr Pro Lys Leu Glu
1170 1175 1180
Ser Glu Phe Val Tyr Gly Asp Tyr Lys Val Tyr Asp Val Arg Lys Met
1185 1190 1195 1200
Ile Ala Lys Ser Glu Gln Glu Ile Gly Lys Ala Thr Ala Lys Tyr Phe
1205 1210 1215
Phe Tyr Ser Asn Ile Met Asn Phe Phe Lys Thr Glu Ile Thr Leu Ala
1220 1225 1230
Asn Gly Glu Ile Arg Lys Arg Pro Leu Ile Glu Thr Asn Gly Glu Thr
1235 1240 1245
Gly Glu Ile Val Trp Asp Lys Gly Arg Asp Phe Ala Thr Val Arg Lys
1250 1255 1260
Val Leu Ser Met Pro Gln Val Asn Ile Val Lys Lys Thr Glu Val Gln
1265 1270 1275 1280
Thr Gly Gly Phe Ser Lys Glu Ser Ile Leu Pro Lys Arg Asn Ser Asp
1285 1290 1295
Lys Leu Ile Ala Arg Lys Lys Asp Trp Asp Pro Lys Lys Tyr Gly Gly
1300 1305 1310
Phe Asp Ser Pro Thr Val Ala Tyr Ser Val Leu Val Val Ala Lys Val
1315 1320 1325
Glu Lys Gly Lys Ser Lys Lys Leu Lys Ser Val Lys Glu Leu Leu Gly
1330 1335 1340
Ile Thr Ile Met Glu Arg Ser Ser Phe Glu Lys Asn Pro Ile Asp Phe
1345 1350 1355 1360
Leu Glu Ala Lys Gly Tyr Lys Glu Val Lys Lys Asp Leu Ile Ile Lys
1365 1370 1375
Leu Pro Lys Tyr Ser Leu Phe Glu Leu Glu Asn Gly Arg Lys Arg Met
1380 1385 1390
Leu Ala Ser Ala Gly Glu Leu Gln Lys Gly Asn Glu Leu Ala Leu Pro
1395 1400 1405
Ser Lys Tyr Val Asn Phe Leu Tyr Leu Ala Ser His Tyr Glu Lys Leu
1410 1415 1420
Lys Gly Ser Pro Glu Asp Asn Glu Gln Lys Gln Leu Phe Val Glu Gln
1425 1430 1435 1440
His Lys His Tyr Leu Asp Glu Ile Ile Glu Gln Ile Ser Glu Phe Ser
1445 1450 1455
Lys Arg Val Ile Leu Ala Asp Ala Asn Leu Asp Lys Val Leu Ser Ala
1460 1465 1470
Tyr Asn Lys His Arg Asp Lys Pro Ile Arg Glu Gln Ala Glu Asn Ile
1475 1480 1485
Ile His Leu Phe Thr Leu Thr Asn Leu Gly Ala Pro Ala Ala Phe Lys
1490 1495 1500
Tyr Phe Asp Thr Thr Ile Asp Arg Lys Arg Tyr Thr Ser Thr Lys Glu
1505 1510 1515 1520
Val Leu Asp Ala Thr Leu Ile His Gln Ser Ile Thr Gly Leu Tyr Glu
1525 1530 1535
Thr Arg Ile Asp Leu Ser Gln Leu Gly Gly Asp
1540 1545
<210> 7
<211> 4647
<212> DNA
<213> g
<400> 7
atgggcagca gccatcatca tcatcatcac tcggaggtcg agttttcaca tgagtattgg 60
atgcgtcatg ccttgacgtt ggcgaaacgg gcgcgcgatg agcgtgaggt gcccgtggga 120
gcggtgttgg tactgaataa ccgggttata ggggaaggat ggaaccgggc tattgggtta 180
cacgacccaa cggcgcacgc cgagataatg gcactgcgcc aagggggctt agttatgcag 240
aattatcgcc ttatcgatgc tacactgtat gtaacctttg aaccctgcgt aatgtgtgcg 300
ggggctatga tccactcgag aatagggcgc gtggtattcg gcgtacgcaa cagcaaacgt 360
ggggctgcgg gctcgttgat gaacgttctg aactaccccg gaatgaatca cagagtagag 420
atcacggagg gaattttggc cgacgaatgt gcagctttac tgtgcgattt ttatcggatg 480
ccgcggcaag tcttcaacgc acagaagaag gctcaatctt ccattaacaa caaaacctat 540
ccgccggata agaaatactc aataggctta gctatcggca caaacagcgt cggctgggcc 600
gtcattacgg acgagtacaa ggtgccgagc aaaaaattca aagttctggg caataccgat 660
cgccacagca taaagaagaa cctcattggc gccctcctgt tcgactccgg ggagacggcc 720
gaagccacgc ggctcaaaag aacagcacgg cgcagatata cccgcagaaa gaatcggatc 780
tgctacctgc aggagatctt tagtaatgag atggctaagg tggatgactc tttcttccat 840
aggctggagg agtccttttt ggtggaggag gataaaaagc acgagcgcca cccaatcttt 900
ggcaatatcg tggacgaggt ggcgtaccat gaaaagtacc caaccatata tcatctgagg 960
aagaagcttg tagacagtac tgataaggct gacttgcggt tgatctatct cgcgctggcg 1020
catatgatca aatttcgggg acacttcctc atcgaggggg acctgaaccc agacaacagc 1080
gatgtcgaca aactctttat ccaactggtt cagacttaca atcagctttt cgaagagaac 1140
ccgatcaacg catccggagt tgacgccaaa gcaatcctga gcgctaggct gtccaaatcc 1200
cggcggctcg aaaacctcat cgcacagctc cctggggaga agaagaacgg cctgtttggt 1260
aatcttatcg ccctgtcact cgggctgacc cccaacttta aatctaactt cgacctggcc 1320
gaagatgcca agcttcaact gagcaaagac acctacgatg atgatctcga caatctgctg 1380
gcccagatcg gcgaccagta cgcagacctt tttttggcgg caaagaacct gtcagacgcc 1440
attctgctga gtgatattct gcgagtgaac acggagatca ccaaagctcc gctgagcgct 1500
agtatgatca agcgctatga tgagcaccac caagacttga ctttgctgaa ggcccttgtc 1560
agacagcaac tgcctgagaa gtacaaggaa attttcttcg atcagtctaa aaatggctac 1620
gccggataca ttgacggcgg agcaagccag gaggaatttt acaaatttat taagcccatc 1680
ttggaaaaaa tggacggcac cgaggagctg ctggtaaagc ttaacagaga agatctgttg 1740
cgcaaacagc gcactttcga caatggaagc atcccccacc agattcacct gggcgaactg 1800
cacgctatcc tcaggcggca agaggatttc tacccctttt tgaaagataa cagggaaaag 1860
attgagaaaa tcctcacatt tcggataccc tactatgtag gccccctcgc ccggggaaat 1920
tccagattcg cgtggatgac tcgcaaatca gaagagacca tcactccctg gaacttcgag 1980
gaagtcgtgg ataagggggc ctctgcccag tccttcatcg aaaggatgac taactttgat 2040
aaaaatctgc ctaacgaaaa ggtgcttcct aaacactctc tgctgtacga gtacttcaca 2100
gtttataacg agctcaccaa ggtcaaatac gtcacagaag ggatgagaaa gccagcattc 2160
ctgtctggag agcagaagaa agctatcgtg gacctcctct tcaagacgaa ccggaaagtt 2220
accgtgaaac agctcaaaga agactatttc aaaaagattg aatgtttcga ctctgttgaa 2280
atcagcggag tggaggatcg cttcaacgca tccctgggaa cgtatcacga tctcctgaaa 2340
atcattaaag acaaggactt cctggacaat gaggagaacg aggacattct tgaggacatt 2400
gtcctcaccc ttacgttgtt tgaagatagg gagatgattg aagaacgctt gaaaacttac 2460
gctcatctct tcgacgacaa agtcatgaaa cagctcaaga ggcgccgata tacaggatgg 2520
gggcggctgt caagaaaact gatcaatggg atccgagaca agcagagtgg aaagacaatc 2580
ctggattttc ttaagtccga tggatttgcc aaccggaact tcatgcagtt gatccatgat 2640
gactctctca cctttaagga ggacatccag aaagcacaag tttctggcca gggggacagt 2700
cttcacgagc acatcgctaa tcttgcaggt agcccagcta tcaaaaaggg aatactgcag 2760
accgttaagg tcgtggatga actcgtcaaa gtaatgggaa ggcataagcc cgagaatatc 2820
gttatcgaga tggcccgaga gaaccaaact acccagaagg gacagaagaa cagtagggaa 2880
aggatgaaga ggattgaaga gggtataaaa gaactggggt cccaaatcct taaggaacac 2940
ccagttgaaa acacccagct tcagaatgag aagctctacc tgtactacct gcagaacggc 3000
agggacatgt acgtggatca ggaactggac atcaatcggc tctccgacta cgacgtggat 3060
catatcgtgc cccagtcttt tctcaaagat gattctattg ataataaagt gttgacaaga 3120
tccgataaaa atagagggaa gagtgataac gtcccctcag aagaagttgt caagaaaatg 3180
aaaaattatt ggcggcagct gctgaacgcc aaactgatca cacaacggaa gttcgataat 3240
ctgactaagg ctgaacgagg tggcctgtct gagttggata aagcaggctt catcaaaagg 3300
cagcttgttg agacacgcca gatcaccaag cacgtggccc aaattctcga ttcacgcatg 3360
aacaccaagt acgatgaaaa tgacaaactg attcgagagg tgaaagttat tactctgaag 3420
tctaagctgg tctcagattt cagaaaggac tttcagtttt ataaggtgag agagatcaac 3480
aattaccacc atgcgcatga tgcctacctg aatgcagtgg taggcactgc acttatcaaa 3540
aaatatccca agcttgaatc tgaatttgtt tacggagact ataaagtgta cgatgttagg 3600
aaaatgatcg caaagtctga gcaggaaata ggcaaggcca ccgctaagta cttcttttac 3660
agcaatatta tgaatttttt caagaccgag attacactgg ccaatggaga gattcggaag 3720
cgaccactta tcgaaacaaa cggagaaaca ggagaaatcg tgtgggacaa gggtagggat 3780
ttcgcgacag tccggaaggt cctgtccatg ccgcaggtga acatcgttaa aaagaccgaa 3840
gtacagaccg gaggcttctc caaggaaagt atcctcccga aaaggaacag cgacaagctg 3900
atcgcacgca aaaaagattg ggaccccaag aaatacggcg gattcgattc tcctacagtc 3960
gcttacagtg tactggttgt ggccaaagtg gagaaaggga agtctaaaaa actcaaaagc 4020
gtcaaggaac tgctgggcat cacaatcatg gagcgatcaa gcttcgaaaa aaaccccatc 4080
gactttctcg aggcgaaagg atataaagag gtcaaaaaag acctcatcat taagcttccc 4140
aagtactctc tctttgagct tgaaaacggc cggaaacgaa tgctcgctag tgcgggcgag 4200
ctgcagaaag gtaacgagct ggcactgccc tctaaatacg ttaatttctt gtatctggcc 4260
agccactatg aaaagctcaa agggtctccc gaagataatg agcagaagca gctgttcgtg 4320
gaacaacaca aacactacct tgatgagatc atcgagcaaa taagcgaatt ctccaaaaga 4380
gtgatcctcg ccgacgctaa cctcgataag gtgctttctg cttacaataa gcacagggat 4440
aagcccatca gggagcaggc agaaaacatt atccacttgt ttactctgac caacttgggc 4500
gcgcctgcag ccttcaagta cttcgacacc accatagaca gaaagcggta cacctctaca 4560
aaggaggtcc tggacgccac actgattcat cagtcaatta cggggctcta tgaaacaaga 4620
atcgacctct ctcagctcgg tggagac 4647
<210> 8
<211> 1549
<212> PRT
<213> h
<400> 8
Met Gly Ser Ser His His His His His His Ser Glu Val Glu Phe Ser
1 5 10 15
His Glu Tyr Trp Met Arg His Ala Leu Thr Leu Ala Lys Arg Ala Arg
20 25 30
Asp Glu Arg Glu Val Pro Val Gly Ala Val Leu Val Leu Asn Asn Arg
35 40 45
Val Ile Gly Glu Gly Trp Asn Arg Ala Ile Gly Leu His Asp Pro Thr
50 55 60
Ala His Ala Glu Ile Met Ala Leu Arg Gln Gly Gly Leu Val Met Gln
65 70 75 80
Asn Tyr Arg Leu Ile Asp Ala Thr Leu Tyr Val Thr Phe Glu Pro Cys
85 90 95
Val Met Cys Ala Gly Ala Met Ile His Ser Arg Ile Gly Arg Val Val
100 105 110
Phe Gly Val Arg Asn Ser Lys Arg Gly Ala Ala Gly Ser Leu Met Asn
115 120 125
Val Leu Asn Tyr Pro Gly Met Asn His Arg Val Glu Ile Thr Glu Gly
130 135 140
Ile Leu Ala Asp Glu Cys Ala Ala Leu Leu Cys Asp Phe Tyr Arg Met
145 150 155 160
Pro Arg Gln Val Phe Asn Ala Gln Lys Lys Ala Gln Ser Ser Ile Asn
165 170 175
Asn Lys Thr Tyr Pro Pro Asp Lys Lys Tyr Ser Ile Gly Leu Ala Ile
180 185 190
Gly Thr Asn Ser Val Gly Trp Ala Val Ile Thr Asp Glu Tyr Lys Val
195 200 205
Pro Ser Lys Lys Phe Lys Val Leu Gly Asn Thr Asp Arg His Ser Ile
210 215 220
Lys Lys Asn Leu Ile Gly Ala Leu Leu Phe Asp Ser Gly Glu Thr Ala
225 230 235 240
Glu Ala Thr Arg Leu Lys Arg Thr Ala Arg Arg Arg Tyr Thr Arg Arg
245 250 255
Lys Asn Arg Ile Cys Tyr Leu Gln Glu Ile Phe Ser Asn Glu Met Ala
260 265 270
Lys Val Asp Asp Ser Phe Phe His Arg Leu Glu Glu Ser Phe Leu Val
275 280 285
Glu Glu Asp Lys Lys His Glu Arg His Pro Ile Phe Gly Asn Ile Val
290 295 300
Asp Glu Val Ala Tyr His Glu Lys Tyr Pro Thr Ile Tyr His Leu Arg
305 310 315 320
Lys Lys Leu Val Asp Ser Thr Asp Lys Ala Asp Leu Arg Leu Ile Tyr
325 330 335
Leu Ala Leu Ala His Met Ile Lys Phe Arg Gly His Phe Leu Ile Glu
340 345 350
Gly Asp Leu Asn Pro Asp Asn Ser Asp Val Asp Lys Leu Phe Ile Gln
355 360 365
Leu Val Gln Thr Tyr Asn Gln Leu Phe Glu Glu Asn Pro Ile Asn Ala
370 375 380
Ser Gly Val Asp Ala Lys Ala Ile Leu Ser Ala Arg Leu Ser Lys Ser
385 390 395 400
Arg Arg Leu Glu Asn Leu Ile Ala Gln Leu Pro Gly Glu Lys Lys Asn
405 410 415
Gly Leu Phe Gly Asn Leu Ile Ala Leu Ser Leu Gly Leu Thr Pro Asn
420 425 430
Phe Lys Ser Asn Phe Asp Leu Ala Glu Asp Ala Lys Leu Gln Leu Ser
435 440 445
Lys Asp Thr Tyr Asp Asp Asp Leu Asp Asn Leu Leu Ala Gln Ile Gly
450 455 460
Asp Gln Tyr Ala Asp Leu Phe Leu Ala Ala Lys Asn Leu Ser Asp Ala
465 470 475 480
Ile Leu Leu Ser Asp Ile Leu Arg Val Asn Thr Glu Ile Thr Lys Ala
485 490 495
Pro Leu Ser Ala Ser Met Ile Lys Arg Tyr Asp Glu His His Gln Asp
500 505 510
Leu Thr Leu Leu Lys Ala Leu Val Arg Gln Gln Leu Pro Glu Lys Tyr
515 520 525
Lys Glu Ile Phe Phe Asp Gln Ser Lys Asn Gly Tyr Ala Gly Tyr Ile
530 535 540
Asp Gly Gly Ala Ser Gln Glu Glu Phe Tyr Lys Phe Ile Lys Pro Ile
545 550 555 560
Leu Glu Lys Met Asp Gly Thr Glu Glu Leu Leu Val Lys Leu Asn Arg
565 570 575
Glu Asp Leu Leu Arg Lys Gln Arg Thr Phe Asp Asn Gly Ser Ile Pro
580 585 590
His Gln Ile His Leu Gly Glu Leu His Ala Ile Leu Arg Arg Gln Glu
595 600 605
Asp Phe Tyr Pro Phe Leu Lys Asp Asn Arg Glu Lys Ile Glu Lys Ile
610 615 620
Leu Thr Phe Arg Ile Pro Tyr Tyr Val Gly Pro Leu Ala Arg Gly Asn
625 630 635 640
Ser Arg Phe Ala Trp Met Thr Arg Lys Ser Glu Glu Thr Ile Thr Pro
645 650 655
Trp Asn Phe Glu Glu Val Val Asp Lys Gly Ala Ser Ala Gln Ser Phe
660 665 670
Ile Glu Arg Met Thr Asn Phe Asp Lys Asn Leu Pro Asn Glu Lys Val
675 680 685
Leu Pro Lys His Ser Leu Leu Tyr Glu Tyr Phe Thr Val Tyr Asn Glu
690 695 700
Leu Thr Lys Val Lys Tyr Val Thr Glu Gly Met Arg Lys Pro Ala Phe
705 710 715 720
Leu Ser Gly Glu Gln Lys Lys Ala Ile Val Asp Leu Leu Phe Lys Thr
725 730 735
Asn Arg Lys Val Thr Val Lys Gln Leu Lys Glu Asp Tyr Phe Lys Lys
740 745 750
Ile Glu Cys Phe Asp Ser Val Glu Ile Ser Gly Val Glu Asp Arg Phe
755 760 765
Asn Ala Ser Leu Gly Thr Tyr His Asp Leu Leu Lys Ile Ile Lys Asp
770 775 780
Lys Asp Phe Leu Asp Asn Glu Glu Asn Glu Asp Ile Leu Glu Asp Ile
785 790 795 800
Val Leu Thr Leu Thr Leu Phe Glu Asp Arg Glu Met Ile Glu Glu Arg
805 810 815
Leu Lys Thr Tyr Ala His Leu Phe Asp Asp Lys Val Met Lys Gln Leu
820 825 830
Lys Arg Arg Arg Tyr Thr Gly Trp Gly Arg Leu Ser Arg Lys Leu Ile
835 840 845
Asn Gly Ile Arg Asp Lys Gln Ser Gly Lys Thr Ile Leu Asp Phe Leu
850 855 860
Lys Ser Asp Gly Phe Ala Asn Arg Asn Phe Met Gln Leu Ile His Asp
865 870 875 880
Asp Ser Leu Thr Phe Lys Glu Asp Ile Gln Lys Ala Gln Val Ser Gly
885 890 895
Gln Gly Asp Ser Leu His Glu His Ile Ala Asn Leu Ala Gly Ser Pro
900 905 910
Ala Ile Lys Lys Gly Ile Leu Gln Thr Val Lys Val Val Asp Glu Leu
915 920 925
Val Lys Val Met Gly Arg His Lys Pro Glu Asn Ile Val Ile Glu Met
930 935 940
Ala Arg Glu Asn Gln Thr Thr Gln Lys Gly Gln Lys Asn Ser Arg Glu
945 950 955 960
Arg Met Lys Arg Ile Glu Glu Gly Ile Lys Glu Leu Gly Ser Gln Ile
965 970 975
Leu Lys Glu His Pro Val Glu Asn Thr Gln Leu Gln Asn Glu Lys Leu
980 985 990
Tyr Leu Tyr Tyr Leu Gln Asn Gly Arg Asp Met Tyr Val Asp Gln Glu
995 1000 1005
Leu Asp Ile Asn Arg Leu Ser Asp Tyr Asp Val Asp His Ile Val Pro
1010 1015 1020
Gln Ser Phe Leu Lys Asp Asp Ser Ile Asp Asn Lys Val Leu Thr Arg
1025 1030 1035 1040
Ser Asp Lys Asn Arg Gly Lys Ser Asp Asn Val Pro Ser Glu Glu Val
1045 1050 1055
Val Lys Lys Met Lys Asn Tyr Trp Arg Gln Leu Leu Asn Ala Lys Leu
1060 1065 1070
Ile Thr Gln Arg Lys Phe Asp Asn Leu Thr Lys Ala Glu Arg Gly Gly
1075 1080 1085
Leu Ser Glu Leu Asp Lys Ala Gly Phe Ile Lys Arg Gln Leu Val Glu
1090 1095 1100
Thr Arg Gln Ile Thr Lys His Val Ala Gln Ile Leu Asp Ser Arg Met
1105 1110 1115 1120
Asn Thr Lys Tyr Asp Glu Asn Asp Lys Leu Ile Arg Glu Val Lys Val
1125 1130 1135
Ile Thr Leu Lys Ser Lys Leu Val Ser Asp Phe Arg Lys Asp Phe Gln
1140 1145 1150
Phe Tyr Lys Val Arg Glu Ile Asn Asn Tyr His His Ala His Asp Ala
1155 1160 1165
Tyr Leu Asn Ala Val Val Gly Thr Ala Leu Ile Lys Lys Tyr Pro Lys
1170 1175 1180
Leu Glu Ser Glu Phe Val Tyr Gly Asp Tyr Lys Val Tyr Asp Val Arg
1185 1190 1195 1200
Lys Met Ile Ala Lys Ser Glu Gln Glu Ile Gly Lys Ala Thr Ala Lys
1205 1210 1215
Tyr Phe Phe Tyr Ser Asn Ile Met Asn Phe Phe Lys Thr Glu Ile Thr
1220 1225 1230
Leu Ala Asn Gly Glu Ile Arg Lys Arg Pro Leu Ile Glu Thr Asn Gly
1235 1240 1245
Glu Thr Gly Glu Ile Val Trp Asp Lys Gly Arg Asp Phe Ala Thr Val
1250 1255 1260
Arg Lys Val Leu Ser Met Pro Gln Val Asn Ile Val Lys Lys Thr Glu
1265 1270 1275 1280
Val Gln Thr Gly Gly Phe Ser Lys Glu Ser Ile Leu Pro Lys Arg Asn
1285 1290 1295
Ser Asp Lys Leu Ile Ala Arg Lys Lys Asp Trp Asp Pro Lys Lys Tyr
1300 1305 1310
Gly Gly Phe Asp Ser Pro Thr Val Ala Tyr Ser Val Leu Val Val Ala
1315 1320 1325
Lys Val Glu Lys Gly Lys Ser Lys Lys Leu Lys Ser Val Lys Glu Leu
1330 1335 1340
Leu Gly Ile Thr Ile Met Glu Arg Ser Ser Phe Glu Lys Asn Pro Ile
1345 1350 1355 1360
Asp Phe Leu Glu Ala Lys Gly Tyr Lys Glu Val Lys Lys Asp Leu Ile
1365 1370 1375
Ile Lys Leu Pro Lys Tyr Ser Leu Phe Glu Leu Glu Asn Gly Arg Lys
1380 1385 1390
Arg Met Leu Ala Ser Ala Gly Glu Leu Gln Lys Gly Asn Glu Leu Ala
1395 1400 1405
Leu Pro Ser Lys Tyr Val Asn Phe Leu Tyr Leu Ala Ser His Tyr Glu
1410 1415 1420
Lys Leu Lys Gly Ser Pro Glu Asp Asn Glu Gln Lys Gln Leu Phe Val
1425 1430 1435 1440
Glu Gln His Lys His Tyr Leu Asp Glu Ile Ile Glu Gln Ile Ser Glu
1445 1450 1455
Phe Ser Lys Arg Val Ile Leu Ala Asp Ala Asn Leu Asp Lys Val Leu
1460 1465 1470
Ser Ala Tyr Asn Lys His Arg Asp Lys Pro Ile Arg Glu Gln Ala Glu
1475 1480 1485
Asn Ile Ile His Leu Phe Thr Leu Thr Asn Leu Gly Ala Pro Ala Ala
1490 1495 1500
Phe Lys Tyr Phe Asp Thr Thr Ile Asp Arg Lys Arg Tyr Thr Ser Thr
1505 1510 1515 1520
Lys Glu Val Leu Asp Ala Thr Leu Ile His Gln Ser Ile Thr Gly Leu
1525 1530 1535
Tyr Glu Thr Arg Ile Asp Leu Ser Gln Leu Gly Gly Asp
1540 1545
<210> 9
<211> 4650
<212> DNA
<213> i
<400> 9
atgggcagca gccatcatca tcatcatcac tcggaggtcg agttttcaca tgagtattgg 60
atgcgtcatg ccttgacgtt ggcgaaacgg gcgcgcgatg agcgtgaggt gcccgtggga 120
gcggtgttgg tactgaataa ccgggttata ggggaaggat ggaaccgggc tattgggtta 180
cacgacccaa cggcgcacgc cgagataatg gcactgcgcc aagggggctt agttatgcag 240
aattatcgcc ttatcgatgc tacactgtat gtaacctttg aaccctgcgt aatgtgtgcg 300
ggggctatga tccactcgag aatagggcgc gtggtattcg gcgtacgcaa cagcaaacgt 360
ggggctgcgg gctcgttgat gaacgttctg aactaccccg gaatgaatca cagagtagag 420
atcacggagg gaattttggc cgacgaatgt gcagctttac tgtgcgattt ttatcggatg 480
ccgcggcaag tcttcaacgc acagaagaag gctcaatctt ccattaacac caccgaaccg 540
ccggataacg ataagaaata ctcaataggc ttagctatcg gcacaaacag cgtcggctgg 600
gccgtcatta cggacgagta caaggtgccg agcaaaaaat tcaaagttct gggcaatacc 660
gatcgccaca gcataaagaa gaacctcatt ggcgccctcc tgttcgactc cggggagacg 720
gccgaagcca cgcggctcaa aagaacagca cggcgcagat atacccgcag aaagaatcgg 780
atctgctacc tgcaggagat ctttagtaat gagatggcta aggtggatga ctctttcttc 840
cataggctgg aggagtcctt tttggtggag gaggataaaa agcacgagcg ccacccaatc 900
tttggcaata tcgtggacga ggtggcgtac catgaaaagt acccaaccat atatcatctg 960
aggaagaagc ttgtagacag tactgataag gctgacttgc ggttgatcta tctcgcgctg 1020
gcgcatatga tcaaatttcg gggacacttc ctcatcgagg gggacctgaa cccagacaac 1080
agcgatgtcg acaaactctt tatccaactg gttcagactt acaatcagct tttcgaagag 1140
aacccgatca acgcatccgg agttgacgcc aaagcaatcc tgagcgctag gctgtccaaa 1200
tcccggcggc tcgaaaacct catcgcacag ctccctgggg agaagaagaa cggcctgttt 1260
ggtaatctta tcgccctgtc actcgggctg acccccaact ttaaatctaa cttcgacctg 1320
gccgaagatg ccaagcttca actgagcaaa gacacctacg atgatgatct cgacaatctg 1380
ctggcccaga tcggcgacca gtacgcagac ctttttttgg cggcaaagaa cctgtcagac 1440
gccattctgc tgagtgatat tctgcgagtg aacacggaga tcaccaaagc tccgctgagc 1500
gctagtatga tcaagcgcta tgatgagcac caccaagact tgactttgct gaaggccctt 1560
gtcagacagc aactgcctga gaagtacaag gaaattttct tcgatcagtc taaaaatggc 1620
tacgccggat acattgacgg cggagcaagc caggaggaat tttacaaatt tattaagccc 1680
atcttggaaa aaatggacgg caccgaggag ctgctggtaa agcttaacag agaagatctg 1740
ttgcgcaaac agcgcacttt cgacaatgga agcatccccc accagattca cctgggcgaa 1800
ctgcacgcta tcctcaggcg gcaagaggat ttctacccct ttttgaaaga taacagggaa 1860
aagattgaga aaatcctcac atttcggata ccctactatg taggccccct cgcccgggga 1920
aattccagat tcgcgtggat gactcgcaaa tcagaagaga ccatcactcc ctggaacttc 1980
gaggaagtcg tggataaggg ggcctctgcc cagtccttca tcgaaaggat gactaacttt 2040
gataaaaatc tgcctaacga aaaggtgctt cctaaacact ctctgctgta cgagtacttc 2100
acagtttata acgagctcac caaggtcaaa tacgtcacag aagggatgag aaagccagca 2160
ttcctgtctg gagagcagaa gaaagctatc gtggacctcc tcttcaagac gaaccggaaa 2220
gttaccgtga aacagctcaa agaagactat ttcaaaaaga ttgaatgttt cgactctgtt 2280
gaaatcagcg gagtggagga tcgcttcaac gcatccctgg gaacgtatca cgatctcctg 2340
aaaatcatta aagacaagga cttcctggac aatgaggaga acgaggacat tcttgaggac 2400
attgtcctca cccttacgtt gtttgaagat agggagatga ttgaagaacg cttgaaaact 2460
tacgctcatc tcttcgacga caaagtcatg aaacagctca agaggcgccg atatacagga 2520
tgggggcggc tgtcaagaaa actgatcaat gggatccgag acaagcagag tggaaagaca 2580
atcctggatt ttcttaagtc cgatggattt gccaaccgga acttcatgca gttgatccat 2640
gatgactctc tcacctttaa ggaggacatc cagaaagcac aagtttctgg ccagggggac 2700
agtcttcacg agcacatcgc taatcttgca ggtagcccag ctatcaaaaa gggaatactg 2760
cagaccgtta aggtcgtgga tgaactcgtc aaagtaatgg gaaggcataa gcccgagaat 2820
atcgttatcg agatggcccg agagaaccaa actacccaga agggacagaa gaacagtagg 2880
gaaaggatga agaggattga agagggtata aaagaactgg ggtcccaaat ccttaaggaa 2940
cacccagttg aaaacaccca gcttcagaat gagaagctct acctgtacta cctgcagaac 3000
ggcagggaca tgtacgtgga tcaggaactg gacatcaatc ggctctccga ctacgacgtg 3060
gatcatatcg tgccccagtc ttttctcaaa gatgattcta ttgataataa agtgttgaca 3120
agatccgata aaaatagagg gaagagtgat aacgtcccct cagaagaagt tgtcaagaaa 3180
atgaaaaatt attggcggca gctgctgaac gccaaactga tcacacaacg gaagttcgat 3240
aatctgacta aggctgaacg aggtggcctg tctgagttgg ataaagcagg cttcatcaaa 3300
aggcagcttg ttgagacacg ccagatcacc aagcacgtgg cccaaattct cgattcacgc 3360
atgaacacca agtacgatga aaatgacaaa ctgattcgag aggtgaaagt tattactctg 3420
aagtctaagc tggtctcaga tttcagaaag gactttcagt tttataaggt gagagagatc 3480
aacaattacc accatgcgca tgatgcctac ctgaatgcag tggtaggcac tgcacttatc 3540
aaaaaatatc ccaagcttga atctgaattt gtttacggag actataaagt gtacgatgtt 3600
aggaaaatga tcgcaaagtc tgagcaggaa ataggcaagg ccaccgctaa gtacttcttt 3660
tacagcaata ttatgaattt tttcaagacc gagattacac tggccaatgg agagattcgg 3720
aagcgaccac ttatcgaaac aaacggagaa acaggagaaa tcgtgtggga caagggtagg 3780
gatttcgcga cagtccggaa ggtcctgtcc atgccgcagg tgaacatcgt taaaaagacc 3840
gaagtacaga ccggaggctt ctccaaggaa agtatcctcc cgaaaaggaa cagcgacaag 3900
ctgatcgcac gcaaaaaaga ttgggacccc aagaaatacg gcggattcga ttctcctaca 3960
gtcgcttaca gtgtactggt tgtggccaaa gtggagaaag ggaagtctaa aaaactcaaa 4020
agcgtcaagg aactgctggg catcacaatc atggagcgat caagcttcga aaaaaacccc 4080
atcgactttc tcgaggcgaa aggatataaa gaggtcaaaa aagacctcat cattaagctt 4140
cccaagtact ctctctttga gcttgaaaac ggccggaaac gaatgctcgc tagtgcgggc 4200
gagctgcaga aaggtaacga gctggcactg ccctctaaat acgttaattt cttgtatctg 4260
gccagccact atgaaaagct caaagggtct cccgaagata atgagcagaa gcagctgttc 4320
gtggaacaac acaaacacta ccttgatgag atcatcgagc aaataagcga attctccaaa 4380
agagtgatcc tcgccgacgc taacctcgat aaggtgcttt ctgcttacaa taagcacagg 4440
gataagccca tcagggagca ggcagaaaac attatccact tgtttactct gaccaacttg 4500
ggcgcgcctg cagccttcaa gtacttcgac accaccatag acagaaagcg gtacacctct 4560
acaaaggagg tcctggacgc cacactgatt catcagtcaa ttacggggct ctatgaaaca 4620
agaatcgacc tctctcagct cggtggagac 4650
<210> 10
<211> 1550
<212> PRT
<213> j
<400> 10
Met Gly Ser Ser His His His His His His Ser Glu Val Glu Phe Ser
1 5 10 15
His Glu Tyr Trp Met Arg His Ala Leu Thr Leu Ala Lys Arg Ala Arg
20 25 30
Asp Glu Arg Glu Val Pro Val Gly Ala Val Leu Val Leu Asn Asn Arg
35 40 45
Val Ile Gly Glu Gly Trp Asn Arg Ala Ile Gly Leu His Asp Pro Thr
50 55 60
Ala His Ala Glu Ile Met Ala Leu Arg Gln Gly Gly Leu Val Met Gln
65 70 75 80
Asn Tyr Arg Leu Ile Asp Ala Thr Leu Tyr Val Thr Phe Glu Pro Cys
85 90 95
Val Met Cys Ala Gly Ala Met Ile His Ser Arg Ile Gly Arg Val Val
100 105 110
Phe Gly Val Arg Asn Ser Lys Arg Gly Ala Ala Gly Ser Leu Met Asn
115 120 125
Val Leu Asn Tyr Pro Gly Met Asn His Arg Val Glu Ile Thr Glu Gly
130 135 140
Ile Leu Ala Asp Glu Cys Ala Ala Leu Leu Cys Asp Phe Tyr Arg Met
145 150 155 160
Pro Arg Gln Val Phe Asn Ala Gln Lys Lys Ala Gln Ser Ser Ile Asn
165 170 175
Thr Thr Glu Pro Pro Asp Asn Asp Lys Lys Tyr Ser Ile Gly Leu Ala
180 185 190
Ile Gly Thr Asn Ser Val Gly Trp Ala Val Ile Thr Asp Glu Tyr Lys
195 200 205
Val Pro Ser Lys Lys Phe Lys Val Leu Gly Asn Thr Asp Arg His Ser
210 215 220
Ile Lys Lys Asn Leu Ile Gly Ala Leu Leu Phe Asp Ser Gly Glu Thr
225 230 235 240
Ala Glu Ala Thr Arg Leu Lys Arg Thr Ala Arg Arg Arg Tyr Thr Arg
245 250 255
Arg Lys Asn Arg Ile Cys Tyr Leu Gln Glu Ile Phe Ser Asn Glu Met
260 265 270
Ala Lys Val Asp Asp Ser Phe Phe His Arg Leu Glu Glu Ser Phe Leu
275 280 285
Val Glu Glu Asp Lys Lys His Glu Arg His Pro Ile Phe Gly Asn Ile
290 295 300
Val Asp Glu Val Ala Tyr His Glu Lys Tyr Pro Thr Ile Tyr His Leu
305 310 315 320
Arg Lys Lys Leu Val Asp Ser Thr Asp Lys Ala Asp Leu Arg Leu Ile
325 330 335
Tyr Leu Ala Leu Ala His Met Ile Lys Phe Arg Gly His Phe Leu Ile
340 345 350
Glu Gly Asp Leu Asn Pro Asp Asn Ser Asp Val Asp Lys Leu Phe Ile
355 360 365
Gln Leu Val Gln Thr Tyr Asn Gln Leu Phe Glu Glu Asn Pro Ile Asn
370 375 380
Ala Ser Gly Val Asp Ala Lys Ala Ile Leu Ser Ala Arg Leu Ser Lys
385 390 395 400
Ser Arg Arg Leu Glu Asn Leu Ile Ala Gln Leu Pro Gly Glu Lys Lys
405 410 415
Asn Gly Leu Phe Gly Asn Leu Ile Ala Leu Ser Leu Gly Leu Thr Pro
420 425 430
Asn Phe Lys Ser Asn Phe Asp Leu Ala Glu Asp Ala Lys Leu Gln Leu
435 440 445
Ser Lys Asp Thr Tyr Asp Asp Asp Leu Asp Asn Leu Leu Ala Gln Ile
450 455 460
Gly Asp Gln Tyr Ala Asp Leu Phe Leu Ala Ala Lys Asn Leu Ser Asp
465 470 475 480
Ala Ile Leu Leu Ser Asp Ile Leu Arg Val Asn Thr Glu Ile Thr Lys
485 490 495
Ala Pro Leu Ser Ala Ser Met Ile Lys Arg Tyr Asp Glu His His Gln
500 505 510
Asp Leu Thr Leu Leu Lys Ala Leu Val Arg Gln Gln Leu Pro Glu Lys
515 520 525
Tyr Lys Glu Ile Phe Phe Asp Gln Ser Lys Asn Gly Tyr Ala Gly Tyr
530 535 540
Ile Asp Gly Gly Ala Ser Gln Glu Glu Phe Tyr Lys Phe Ile Lys Pro
545 550 555 560
Ile Leu Glu Lys Met Asp Gly Thr Glu Glu Leu Leu Val Lys Leu Asn
565 570 575
Arg Glu Asp Leu Leu Arg Lys Gln Arg Thr Phe Asp Asn Gly Ser Ile
580 585 590
Pro His Gln Ile His Leu Gly Glu Leu His Ala Ile Leu Arg Arg Gln
595 600 605
Glu Asp Phe Tyr Pro Phe Leu Lys Asp Asn Arg Glu Lys Ile Glu Lys
610 615 620
Ile Leu Thr Phe Arg Ile Pro Tyr Tyr Val Gly Pro Leu Ala Arg Gly
625 630 635 640
Asn Ser Arg Phe Ala Trp Met Thr Arg Lys Ser Glu Glu Thr Ile Thr
645 650 655
Pro Trp Asn Phe Glu Glu Val Val Asp Lys Gly Ala Ser Ala Gln Ser
660 665 670
Phe Ile Glu Arg Met Thr Asn Phe Asp Lys Asn Leu Pro Asn Glu Lys
675 680 685
Val Leu Pro Lys His Ser Leu Leu Tyr Glu Tyr Phe Thr Val Tyr Asn
690 695 700
Glu Leu Thr Lys Val Lys Tyr Val Thr Glu Gly Met Arg Lys Pro Ala
705 710 715 720
Phe Leu Ser Gly Glu Gln Lys Lys Ala Ile Val Asp Leu Leu Phe Lys
725 730 735
Thr Asn Arg Lys Val Thr Val Lys Gln Leu Lys Glu Asp Tyr Phe Lys
740 745 750
Lys Ile Glu Cys Phe Asp Ser Val Glu Ile Ser Gly Val Glu Asp Arg
755 760 765
Phe Asn Ala Ser Leu Gly Thr Tyr His Asp Leu Leu Lys Ile Ile Lys
770 775 780
Asp Lys Asp Phe Leu Asp Asn Glu Glu Asn Glu Asp Ile Leu Glu Asp
785 790 795 800
Ile Val Leu Thr Leu Thr Leu Phe Glu Asp Arg Glu Met Ile Glu Glu
805 810 815
Arg Leu Lys Thr Tyr Ala His Leu Phe Asp Asp Lys Val Met Lys Gln
820 825 830
Leu Lys Arg Arg Arg Tyr Thr Gly Trp Gly Arg Leu Ser Arg Lys Leu
835 840 845
Ile Asn Gly Ile Arg Asp Lys Gln Ser Gly Lys Thr Ile Leu Asp Phe
850 855 860
Leu Lys Ser Asp Gly Phe Ala Asn Arg Asn Phe Met Gln Leu Ile His
865 870 875 880
Asp Asp Ser Leu Thr Phe Lys Glu Asp Ile Gln Lys Ala Gln Val Ser
885 890 895
Gly Gln Gly Asp Ser Leu His Glu His Ile Ala Asn Leu Ala Gly Ser
900 905 910
Pro Ala Ile Lys Lys Gly Ile Leu Gln Thr Val Lys Val Val Asp Glu
915 920 925
Leu Val Lys Val Met Gly Arg His Lys Pro Glu Asn Ile Val Ile Glu
930 935 940
Met Ala Arg Glu Asn Gln Thr Thr Gln Lys Gly Gln Lys Asn Ser Arg
945 950 955 960
Glu Arg Met Lys Arg Ile Glu Glu Gly Ile Lys Glu Leu Gly Ser Gln
965 970 975
Ile Leu Lys Glu His Pro Val Glu Asn Thr Gln Leu Gln Asn Glu Lys
980 985 990
Leu Tyr Leu Tyr Tyr Leu Gln Asn Gly Arg Asp Met Tyr Val Asp Gln
995 1000 1005
Glu Leu Asp Ile Asn Arg Leu Ser Asp Tyr Asp Val Asp His Ile Val
1010 1015 1020
Pro Gln Ser Phe Leu Lys Asp Asp Ser Ile Asp Asn Lys Val Leu Thr
1025 1030 1035 1040
Arg Ser Asp Lys Asn Arg Gly Lys Ser Asp Asn Val Pro Ser Glu Glu
1045 1050 1055
Val Val Lys Lys Met Lys Asn Tyr Trp Arg Gln Leu Leu Asn Ala Lys
1060 1065 1070
Leu Ile Thr Gln Arg Lys Phe Asp Asn Leu Thr Lys Ala Glu Arg Gly
1075 1080 1085
Gly Leu Ser Glu Leu Asp Lys Ala Gly Phe Ile Lys Arg Gln Leu Val
1090 1095 1100
Glu Thr Arg Gln Ile Thr Lys His Val Ala Gln Ile Leu Asp Ser Arg
1105 1110 1115 1120
Met Asn Thr Lys Tyr Asp Glu Asn Asp Lys Leu Ile Arg Glu Val Lys
1125 1130 1135
Val Ile Thr Leu Lys Ser Lys Leu Val Ser Asp Phe Arg Lys Asp Phe
1140 1145 1150
Gln Phe Tyr Lys Val Arg Glu Ile Asn Asn Tyr His His Ala His Asp
1155 1160 1165
Ala Tyr Leu Asn Ala Val Val Gly Thr Ala Leu Ile Lys Lys Tyr Pro
1170 1175 1180
Lys Leu Glu Ser Glu Phe Val Tyr Gly Asp Tyr Lys Val Tyr Asp Val
1185 1190 1195 1200
Arg Lys Met Ile Ala Lys Ser Glu Gln Glu Ile Gly Lys Ala Thr Ala
1205 1210 1215
Lys Tyr Phe Phe Tyr Ser Asn Ile Met Asn Phe Phe Lys Thr Glu Ile
1220 1225 1230
Thr Leu Ala Asn Gly Glu Ile Arg Lys Arg Pro Leu Ile Glu Thr Asn
1235 1240 1245
Gly Glu Thr Gly Glu Ile Val Trp Asp Lys Gly Arg Asp Phe Ala Thr
1250 1255 1260
Val Arg Lys Val Leu Ser Met Pro Gln Val Asn Ile Val Lys Lys Thr
1265 1270 1275 1280
Glu Val Gln Thr Gly Gly Phe Ser Lys Glu Ser Ile Leu Pro Lys Arg
1285 1290 1295
Asn Ser Asp Lys Leu Ile Ala Arg Lys Lys Asp Trp Asp Pro Lys Lys
1300 1305 1310
Tyr Gly Gly Phe Asp Ser Pro Thr Val Ala Tyr Ser Val Leu Val Val
1315 1320 1325
Ala Lys Val Glu Lys Gly Lys Ser Lys Lys Leu Lys Ser Val Lys Glu
1330 1335 1340
Leu Leu Gly Ile Thr Ile Met Glu Arg Ser Ser Phe Glu Lys Asn Pro
1345 1350 1355 1360
Ile Asp Phe Leu Glu Ala Lys Gly Tyr Lys Glu Val Lys Lys Asp Leu
1365 1370 1375
Ile Ile Lys Leu Pro Lys Tyr Ser Leu Phe Glu Leu Glu Asn Gly Arg
1380 1385 1390
Lys Arg Met Leu Ala Ser Ala Gly Glu Leu Gln Lys Gly Asn Glu Leu
1395 1400 1405
Ala Leu Pro Ser Lys Tyr Val Asn Phe Leu Tyr Leu Ala Ser His Tyr
1410 1415 1420
Glu Lys Leu Lys Gly Ser Pro Glu Asp Asn Glu Gln Lys Gln Leu Phe
1425 1430 1435 1440
Val Glu Gln His Lys His Tyr Leu Asp Glu Ile Ile Glu Gln Ile Ser
1445 1450 1455
Glu Phe Ser Lys Arg Val Ile Leu Ala Asp Ala Asn Leu Asp Lys Val
1460 1465 1470
Leu Ser Ala Tyr Asn Lys His Arg Asp Lys Pro Ile Arg Glu Gln Ala
1475 1480 1485
Glu Asn Ile Ile His Leu Phe Thr Leu Thr Asn Leu Gly Ala Pro Ala
1490 1495 1500
Ala Phe Lys Tyr Phe Asp Thr Thr Ile Asp Arg Lys Arg Tyr Thr Ser
1505 1510 1515 1520
Thr Lys Glu Val Leu Asp Ala Thr Leu Ile His Gln Ser Ile Thr Gly
1525 1530 1535
Leu Tyr Glu Thr Arg Ile Asp Leu Ser Gln Leu Gly Gly Asp
1540 1545 1550
<210> 11
<211> 4650
<212> DNA
<213> k
<400> 11
atgggcagca gccatcatca tcatcatcac tcggaggtcg agttttcaca tgagtattgg 60
atgcgtcatg ccttgacgtt ggcgaaacgg gcgcgcgatg agcgtgaggt gcccgtggga 120
gcggtgttgg tactgaataa ccgggttata ggggaaggat ggaaccgggc tattgggtta 180
cacgacccaa cggcgcacgc cgagataatg gcactgcgcc aagggggctt agttatgcag 240
aattatcgcc ttatcgatgc tacactgtat gtaacctttg aaccctgcgt aatgtgtgcg 300
ggggctatga tccactcgag aatagggcgc gtggtattcg gcgtacgcaa cagcaaacgt 360
ggggctgcgg gctcgttgat gaacgttctg aactaccccg gaatgaatca cagagtagag 420
atcacggagg gaattttggc cgacgaatgt gcagctttac tgtgcgattt ttatcggatg 480
ccgcggcaag tcttcaacgc acagaagaag gctcaatctt ccattaaccc ggcgccggcg 540
ccggcgccgg ataagaaata ctcaataggc ttagctatcg gcacaaacag cgtcggctgg 600
gccgtcatta cggacgagta caaggtgccg agcaaaaaat tcaaagttct gggcaatacc 660
gatcgccaca gcataaagaa gaacctcatt ggcgccctcc tgttcgactc cggggagacg 720
gccgaagcca cgcggctcaa aagaacagca cggcgcagat atacccgcag aaagaatcgg 780
atctgctacc tgcaggagat ctttagtaat gagatggcta aggtggatga ctctttcttc 840
cataggctgg aggagtcctt tttggtggag gaggataaaa agcacgagcg ccacccaatc 900
tttggcaata tcgtggacga ggtggcgtac catgaaaagt acccaaccat atatcatctg 960
aggaagaagc ttgtagacag tactgataag gctgacttgc ggttgatcta tctcgcgctg 1020
gcgcatatga tcaaatttcg gggacacttc ctcatcgagg gggacctgaa cccagacaac 1080
agcgatgtcg acaaactctt tatccaactg gttcagactt acaatcagct tttcgaagag 1140
aacccgatca acgcatccgg agttgacgcc aaagcaatcc tgagcgctag gctgtccaaa 1200
tcccggcggc tcgaaaacct catcgcacag ctccctgggg agaagaagaa cggcctgttt 1260
ggtaatctta tcgccctgtc actcgggctg acccccaact ttaaatctaa cttcgacctg 1320
gccgaagatg ccaagcttca actgagcaaa gacacctacg atgatgatct cgacaatctg 1380
ctggcccaga tcggcgacca gtacgcagac ctttttttgg cggcaaagaa cctgtcagac 1440
gccattctgc tgagtgatat tctgcgagtg aacacggaga tcaccaaagc tccgctgagc 1500
gctagtatga tcaagcgcta tgatgagcac caccaagact tgactttgct gaaggccctt 1560
gtcagacagc aactgcctga gaagtacaag gaaattttct tcgatcagtc taaaaatggc 1620
tacgccggat acattgacgg cggagcaagc caggaggaat tttacaaatt tattaagccc 1680
atcttggaaa aaatggacgg caccgaggag ctgctggtaa agcttaacag agaagatctg 1740
ttgcgcaaac agcgcacttt cgacaatgga agcatccccc accagattca cctgggcgaa 1800
ctgcacgcta tcctcaggcg gcaagaggat ttctacccct ttttgaaaga taacagggaa 1860
aagattgaga aaatcctcac atttcggata ccctactatg taggccccct cgcccgggga 1920
aattccagat tcgcgtggat gactcgcaaa tcagaagaga ccatcactcc ctggaacttc 1980
gaggaagtcg tggataaggg ggcctctgcc cagtccttca tcgaaaggat gactaacttt 2040
gataaaaatc tgcctaacga aaaggtgctt cctaaacact ctctgctgta cgagtacttc 2100
acagtttata acgagctcac caaggtcaaa tacgtcacag aagggatgag aaagccagca 2160
ttcctgtctg gagagcagaa gaaagctatc gtggacctcc tcttcaagac gaaccggaaa 2220
gttaccgtga aacagctcaa agaagactat ttcaaaaaga ttgaatgttt cgactctgtt 2280
gaaatcagcg gagtggagga tcgcttcaac gcatccctgg gaacgtatca cgatctcctg 2340
aaaatcatta aagacaagga cttcctggac aatgaggaga acgaggacat tcttgaggac 2400
attgtcctca cccttacgtt gtttgaagat agggagatga ttgaagaacg cttgaaaact 2460
tacgctcatc tcttcgacga caaagtcatg aaacagctca agaggcgccg atatacagga 2520
tgggggcggc tgtcaagaaa actgatcaat gggatccgag acaagcagag tggaaagaca 2580
atcctggatt ttcttaagtc cgatggattt gccaaccgga acttcatgca gttgatccat 2640
gatgactctc tcacctttaa ggaggacatc cagaaagcac aagtttctgg ccagggggac 2700
agtcttcacg agcacatcgc taatcttgca ggtagcccag ctatcaaaaa gggaatactg 2760
cagaccgtta aggtcgtgga tgaactcgtc aaagtaatgg gaaggcataa gcccgagaat 2820
atcgttatcg agatggcccg agagaaccaa actacccaga agggacagaa gaacagtagg 2880
gaaaggatga agaggattga agagggtata aaagaactgg ggtcccaaat ccttaaggaa 2940
cacccagttg aaaacaccca gcttcagaat gagaagctct acctgtacta cctgcagaac 3000
ggcagggaca tgtacgtgga tcaggaactg gacatcaatc ggctctccga ctacgacgtg 3060
gatcatatcg tgccccagtc ttttctcaaa gatgattcta ttgataataa agtgttgaca 3120
agatccgata aaaatagagg gaagagtgat aacgtcccct cagaagaagt tgtcaagaaa 3180
atgaaaaatt attggcggca gctgctgaac gccaaactga tcacacaacg gaagttcgat 3240
aatctgacta aggctgaacg aggtggcctg tctgagttgg ataaagcagg cttcatcaaa 3300
aggcagcttg ttgagacacg ccagatcacc aagcacgtgg cccaaattct cgattcacgc 3360
atgaacacca agtacgatga aaatgacaaa ctgattcgag aggtgaaagt tattactctg 3420
aagtctaagc tggtctcaga tttcagaaag gactttcagt tttataaggt gagagagatc 3480
aacaattacc accatgcgca tgatgcctac ctgaatgcag tggtaggcac tgcacttatc 3540
aaaaaatatc ccaagcttga atctgaattt gtttacggag actataaagt gtacgatgtt 3600
aggaaaatga tcgcaaagtc tgagcaggaa ataggcaagg ccaccgctaa gtacttcttt 3660
tacagcaata ttatgaattt tttcaagacc gagattacac tggccaatgg agagattcgg 3720
aagcgaccac ttatcgaaac aaacggagaa acaggagaaa tcgtgtggga caagggtagg 3780
gatttcgcga cagtccggaa ggtcctgtcc atgccgcagg tgaacatcgt taaaaagacc 3840
gaagtacaga ccggaggctt ctccaaggaa agtatcctcc cgaaaaggaa cagcgacaag 3900
ctgatcgcac gcaaaaaaga ttgggacccc aagaaatacg gcggattcga ttctcctaca 3960
gtcgcttaca gtgtactggt tgtggccaaa gtggagaaag ggaagtctaa aaaactcaaa 4020
agcgtcaagg aactgctggg catcacaatc atggagcgat caagcttcga aaaaaacccc 4080
atcgactttc tcgaggcgaa aggatataaa gaggtcaaaa aagacctcat cattaagctt 4140
cccaagtact ctctctttga gcttgaaaac ggccggaaac gaatgctcgc tagtgcgggc 4200
gagctgcaga aaggtaacga gctggcactg ccctctaaat acgttaattt cttgtatctg 4260
gccagccact atgaaaagct caaagggtct cccgaagata atgagcagaa gcagctgttc 4320
gtggaacaac acaaacacta ccttgatgag atcatcgagc aaataagcga attctccaaa 4380
agagtgatcc tcgccgacgc taacctcgat aaggtgcttt ctgcttacaa taagcacagg 4440
gataagccca tcagggagca ggcagaaaac attatccact tgtttactct gaccaacttg 4500
ggcgcgcctg cagccttcaa gtacttcgac accaccatag acagaaagcg gtacacctct 4560
acaaaggagg tcctggacgc cacactgatt catcagtcaa ttacggggct ctatgaaaca 4620
agaatcgacc tctctcagct cggtggagac 4650
<210> 12
<211> 1550
<212> PRT
<213> l
<400> 12
Met Gly Ser Ser His His His His His His Ser Glu Val Glu Phe Ser
1 5 10 15
His Glu Tyr Trp Met Arg His Ala Leu Thr Leu Ala Lys Arg Ala Arg
20 25 30
Asp Glu Arg Glu Val Pro Val Gly Ala Val Leu Val Leu Asn Asn Arg
35 40 45
Val Ile Gly Glu Gly Trp Asn Arg Ala Ile Gly Leu His Asp Pro Thr
50 55 60
Ala His Ala Glu Ile Met Ala Leu Arg Gln Gly Gly Leu Val Met Gln
65 70 75 80
Asn Tyr Arg Leu Ile Asp Ala Thr Leu Tyr Val Thr Phe Glu Pro Cys
85 90 95
Val Met Cys Ala Gly Ala Met Ile His Ser Arg Ile Gly Arg Val Val
100 105 110
Phe Gly Val Arg Asn Ser Lys Arg Gly Ala Ala Gly Ser Leu Met Asn
115 120 125
Val Leu Asn Tyr Pro Gly Met Asn His Arg Val Glu Ile Thr Glu Gly
130 135 140
Ile Leu Ala Asp Glu Cys Ala Ala Leu Leu Cys Asp Phe Tyr Arg Met
145 150 155 160
Pro Arg Gln Val Phe Asn Ala Gln Lys Lys Ala Gln Ser Ser Ile Asn
165 170 175
Pro Ala Pro Ala Pro Ala Pro Asp Lys Lys Tyr Ser Ile Gly Leu Ala
180 185 190
Ile Gly Thr Asn Ser Val Gly Trp Ala Val Ile Thr Asp Glu Tyr Lys
195 200 205
Val Pro Ser Lys Lys Phe Lys Val Leu Gly Asn Thr Asp Arg His Ser
210 215 220
Ile Lys Lys Asn Leu Ile Gly Ala Leu Leu Phe Asp Ser Gly Glu Thr
225 230 235 240
Ala Glu Ala Thr Arg Leu Lys Arg Thr Ala Arg Arg Arg Tyr Thr Arg
245 250 255
Arg Lys Asn Arg Ile Cys Tyr Leu Gln Glu Ile Phe Ser Asn Glu Met
260 265 270
Ala Lys Val Asp Asp Ser Phe Phe His Arg Leu Glu Glu Ser Phe Leu
275 280 285
Val Glu Glu Asp Lys Lys His Glu Arg His Pro Ile Phe Gly Asn Ile
290 295 300
Val Asp Glu Val Ala Tyr His Glu Lys Tyr Pro Thr Ile Tyr His Leu
305 310 315 320
Arg Lys Lys Leu Val Asp Ser Thr Asp Lys Ala Asp Leu Arg Leu Ile
325 330 335
Tyr Leu Ala Leu Ala His Met Ile Lys Phe Arg Gly His Phe Leu Ile
340 345 350
Glu Gly Asp Leu Asn Pro Asp Asn Ser Asp Val Asp Lys Leu Phe Ile
355 360 365
Gln Leu Val Gln Thr Tyr Asn Gln Leu Phe Glu Glu Asn Pro Ile Asn
370 375 380
Ala Ser Gly Val Asp Ala Lys Ala Ile Leu Ser Ala Arg Leu Ser Lys
385 390 395 400
Ser Arg Arg Leu Glu Asn Leu Ile Ala Gln Leu Pro Gly Glu Lys Lys
405 410 415
Asn Gly Leu Phe Gly Asn Leu Ile Ala Leu Ser Leu Gly Leu Thr Pro
420 425 430
Asn Phe Lys Ser Asn Phe Asp Leu Ala Glu Asp Ala Lys Leu Gln Leu
435 440 445
Ser Lys Asp Thr Tyr Asp Asp Asp Leu Asp Asn Leu Leu Ala Gln Ile
450 455 460
Gly Asp Gln Tyr Ala Asp Leu Phe Leu Ala Ala Lys Asn Leu Ser Asp
465 470 475 480
Ala Ile Leu Leu Ser Asp Ile Leu Arg Val Asn Thr Glu Ile Thr Lys
485 490 495
Ala Pro Leu Ser Ala Ser Met Ile Lys Arg Tyr Asp Glu His His Gln
500 505 510
Asp Leu Thr Leu Leu Lys Ala Leu Val Arg Gln Gln Leu Pro Glu Lys
515 520 525
Tyr Lys Glu Ile Phe Phe Asp Gln Ser Lys Asn Gly Tyr Ala Gly Tyr
530 535 540
Ile Asp Gly Gly Ala Ser Gln Glu Glu Phe Tyr Lys Phe Ile Lys Pro
545 550 555 560
Ile Leu Glu Lys Met Asp Gly Thr Glu Glu Leu Leu Val Lys Leu Asn
565 570 575
Arg Glu Asp Leu Leu Arg Lys Gln Arg Thr Phe Asp Asn Gly Ser Ile
580 585 590
Pro His Gln Ile His Leu Gly Glu Leu His Ala Ile Leu Arg Arg Gln
595 600 605
Glu Asp Phe Tyr Pro Phe Leu Lys Asp Asn Arg Glu Lys Ile Glu Lys
610 615 620
Ile Leu Thr Phe Arg Ile Pro Tyr Tyr Val Gly Pro Leu Ala Arg Gly
625 630 635 640
Asn Ser Arg Phe Ala Trp Met Thr Arg Lys Ser Glu Glu Thr Ile Thr
645 650 655
Pro Trp Asn Phe Glu Glu Val Val Asp Lys Gly Ala Ser Ala Gln Ser
660 665 670
Phe Ile Glu Arg Met Thr Asn Phe Asp Lys Asn Leu Pro Asn Glu Lys
675 680 685
Val Leu Pro Lys His Ser Leu Leu Tyr Glu Tyr Phe Thr Val Tyr Asn
690 695 700
Glu Leu Thr Lys Val Lys Tyr Val Thr Glu Gly Met Arg Lys Pro Ala
705 710 715 720
Phe Leu Ser Gly Glu Gln Lys Lys Ala Ile Val Asp Leu Leu Phe Lys
725 730 735
Thr Asn Arg Lys Val Thr Val Lys Gln Leu Lys Glu Asp Tyr Phe Lys
740 745 750
Lys Ile Glu Cys Phe Asp Ser Val Glu Ile Ser Gly Val Glu Asp Arg
755 760 765
Phe Asn Ala Ser Leu Gly Thr Tyr His Asp Leu Leu Lys Ile Ile Lys
770 775 780
Asp Lys Asp Phe Leu Asp Asn Glu Glu Asn Glu Asp Ile Leu Glu Asp
785 790 795 800
Ile Val Leu Thr Leu Thr Leu Phe Glu Asp Arg Glu Met Ile Glu Glu
805 810 815
Arg Leu Lys Thr Tyr Ala His Leu Phe Asp Asp Lys Val Met Lys Gln
820 825 830
Leu Lys Arg Arg Arg Tyr Thr Gly Trp Gly Arg Leu Ser Arg Lys Leu
835 840 845
Ile Asn Gly Ile Arg Asp Lys Gln Ser Gly Lys Thr Ile Leu Asp Phe
850 855 860
Leu Lys Ser Asp Gly Phe Ala Asn Arg Asn Phe Met Gln Leu Ile His
865 870 875 880
Asp Asp Ser Leu Thr Phe Lys Glu Asp Ile Gln Lys Ala Gln Val Ser
885 890 895
Gly Gln Gly Asp Ser Leu His Glu His Ile Ala Asn Leu Ala Gly Ser
900 905 910
Pro Ala Ile Lys Lys Gly Ile Leu Gln Thr Val Lys Val Val Asp Glu
915 920 925
Leu Val Lys Val Met Gly Arg His Lys Pro Glu Asn Ile Val Ile Glu
930 935 940
Met Ala Arg Glu Asn Gln Thr Thr Gln Lys Gly Gln Lys Asn Ser Arg
945 950 955 960
Glu Arg Met Lys Arg Ile Glu Glu Gly Ile Lys Glu Leu Gly Ser Gln
965 970 975
Ile Leu Lys Glu His Pro Val Glu Asn Thr Gln Leu Gln Asn Glu Lys
980 985 990
Leu Tyr Leu Tyr Tyr Leu Gln Asn Gly Arg Asp Met Tyr Val Asp Gln
995 1000 1005
Glu Leu Asp Ile Asn Arg Leu Ser Asp Tyr Asp Val Asp His Ile Val
1010 1015 1020
Pro Gln Ser Phe Leu Lys Asp Asp Ser Ile Asp Asn Lys Val Leu Thr
1025 1030 1035 1040
Arg Ser Asp Lys Asn Arg Gly Lys Ser Asp Asn Val Pro Ser Glu Glu
1045 1050 1055
Val Val Lys Lys Met Lys Asn Tyr Trp Arg Gln Leu Leu Asn Ala Lys
1060 1065 1070
Leu Ile Thr Gln Arg Lys Phe Asp Asn Leu Thr Lys Ala Glu Arg Gly
1075 1080 1085
Gly Leu Ser Glu Leu Asp Lys Ala Gly Phe Ile Lys Arg Gln Leu Val
1090 1095 1100
Glu Thr Arg Gln Ile Thr Lys His Val Ala Gln Ile Leu Asp Ser Arg
1105 1110 1115 1120
Met Asn Thr Lys Tyr Asp Glu Asn Asp Lys Leu Ile Arg Glu Val Lys
1125 1130 1135
Val Ile Thr Leu Lys Ser Lys Leu Val Ser Asp Phe Arg Lys Asp Phe
1140 1145 1150
Gln Phe Tyr Lys Val Arg Glu Ile Asn Asn Tyr His His Ala His Asp
1155 1160 1165
Ala Tyr Leu Asn Ala Val Val Gly Thr Ala Leu Ile Lys Lys Tyr Pro
1170 1175 1180
Lys Leu Glu Ser Glu Phe Val Tyr Gly Asp Tyr Lys Val Tyr Asp Val
1185 1190 1195 1200
Arg Lys Met Ile Ala Lys Ser Glu Gln Glu Ile Gly Lys Ala Thr Ala
1205 1210 1215
Lys Tyr Phe Phe Tyr Ser Asn Ile Met Asn Phe Phe Lys Thr Glu Ile
1220 1225 1230
Thr Leu Ala Asn Gly Glu Ile Arg Lys Arg Pro Leu Ile Glu Thr Asn
1235 1240 1245
Gly Glu Thr Gly Glu Ile Val Trp Asp Lys Gly Arg Asp Phe Ala Thr
1250 1255 1260
Val Arg Lys Val Leu Ser Met Pro Gln Val Asn Ile Val Lys Lys Thr
1265 1270 1275 1280
Glu Val Gln Thr Gly Gly Phe Ser Lys Glu Ser Ile Leu Pro Lys Arg
1285 1290 1295
Asn Ser Asp Lys Leu Ile Ala Arg Lys Lys Asp Trp Asp Pro Lys Lys
1300 1305 1310
Tyr Gly Gly Phe Asp Ser Pro Thr Val Ala Tyr Ser Val Leu Val Val
1315 1320 1325
Ala Lys Val Glu Lys Gly Lys Ser Lys Lys Leu Lys Ser Val Lys Glu
1330 1335 1340
Leu Leu Gly Ile Thr Ile Met Glu Arg Ser Ser Phe Glu Lys Asn Pro
1345 1350 1355 1360
Ile Asp Phe Leu Glu Ala Lys Gly Tyr Lys Glu Val Lys Lys Asp Leu
1365 1370 1375
Ile Ile Lys Leu Pro Lys Tyr Ser Leu Phe Glu Leu Glu Asn Gly Arg
1380 1385 1390
Lys Arg Met Leu Ala Ser Ala Gly Glu Leu Gln Lys Gly Asn Glu Leu
1395 1400 1405
Ala Leu Pro Ser Lys Tyr Val Asn Phe Leu Tyr Leu Ala Ser His Tyr
1410 1415 1420
Glu Lys Leu Lys Gly Ser Pro Glu Asp Asn Glu Gln Lys Gln Leu Phe
1425 1430 1435 1440
Val Glu Gln His Lys His Tyr Leu Asp Glu Ile Ile Glu Gln Ile Ser
1445 1450 1455
Glu Phe Ser Lys Arg Val Ile Leu Ala Asp Ala Asn Leu Asp Lys Val
1460 1465 1470
Leu Ser Ala Tyr Asn Lys His Arg Asp Lys Pro Ile Arg Glu Gln Ala
1475 1480 1485
Glu Asn Ile Ile His Leu Phe Thr Leu Thr Asn Leu Gly Ala Pro Ala
1490 1495 1500
Ala Phe Lys Tyr Phe Asp Thr Thr Ile Asp Arg Lys Arg Tyr Thr Ser
1505 1510 1515 1520
Thr Lys Glu Val Leu Asp Ala Thr Leu Ile His Gln Ser Ile Thr Gly
1525 1530 1535
Leu Tyr Glu Thr Arg Ile Asp Leu Ser Gln Leu Gly Gly Asp
1540 1545 1550
<210> 13
<211> 4665
<212> DNA
<213> m
<400> 13
atgggcagca gccatcatca tcatcatcac tcggaggtcg agttttcaca tgagtattgg 60
atgcgtcatg ccttgacgtt ggcgaaacgg gcgcgcgatg agcgtgaggt gcccgtggga 120
gcggtgttgg tactgaataa ccgggttata ggggaaggat ggaaccgggc tattgggtta 180
cacgacccaa cggcgcacgc cgagataatg gcactgcgcc aagggggctt agttatgcag 240
aattatcgcc ttatcgatgc tacactgtat gtaacctttg aaccctgcgt aatgtgtgcg 300
ggggctatga tccactcgag aatagggcgc gtggtattcg gcgtacgcaa cagcaaacgt 360
ggggctgcgg gctcgttgat gaacgttctg aactaccccg gaatgaatca cagagtagag 420
atcacggagg gaattttggc cgacgaatgt gcagctttac tgtgcgattt ttatcggatg 480
ccgcggcaag tcttcaacgc acagaagaag gctcaatctt ccattaacgc ggaagcggcg 540
gcgaaagaag cggcggcgaa agcggataag aaatactcaa taggcttagc tatcggcaca 600
aacagcgtcg gctgggccgt cattacggac gagtacaagg tgccgagcaa aaaattcaaa 660
gttctgggca ataccgatcg ccacagcata aagaagaacc tcattggcgc cctcctgttc 720
gactccgggg agacggccga agccacgcgg ctcaaaagaa cagcacggcg cagatatacc 780
cgcagaaaga atcggatctg ctacctgcag gagatcttta gtaatgagat ggctaaggtg 840
gatgactctt tcttccatag gctggaggag tcctttttgg tggaggagga taaaaagcac 900
gagcgccacc caatctttgg caatatcgtg gacgaggtgg cgtaccatga aaagtaccca 960
accatatatc atctgaggaa gaagcttgta gacagtactg ataaggctga cttgcggttg 1020
atctatctcg cgctggcgca tatgatcaaa tttcggggac acttcctcat cgagggggac 1080
ctgaacccag acaacagcga tgtcgacaaa ctctttatcc aactggttca gacttacaat 1140
cagcttttcg aagagaaccc gatcaacgca tccggagttg acgccaaagc aatcctgagc 1200
gctaggctgt ccaaatcccg gcggctcgaa aacctcatcg cacagctccc tggggagaag 1260
aagaacggcc tgtttggtaa tcttatcgcc ctgtcactcg ggctgacccc caactttaaa 1320
tctaacttcg acctggccga agatgccaag cttcaactga gcaaagacac ctacgatgat 1380
gatctcgaca atctgctggc ccagatcggc gaccagtacg cagacctttt tttggcggca 1440
aagaacctgt cagacgccat tctgctgagt gatattctgc gagtgaacac ggagatcacc 1500
aaagctccgc tgagcgctag tatgatcaag cgctatgatg agcaccacca agacttgact 1560
ttgctgaagg cccttgtcag acagcaactg cctgagaagt acaaggaaat tttcttcgat 1620
cagtctaaaa atggctacgc cggatacatt gacggcggag caagccagga ggaattttac 1680
aaatttatta agcccatctt ggaaaaaatg gacggcaccg aggagctgct ggtaaagctt 1740
aacagagaag atctgttgcg caaacagcgc actttcgaca atggaagcat cccccaccag 1800
attcacctgg gcgaactgca cgctatcctc aggcggcaag aggatttcta cccctttttg 1860
aaagataaca gggaaaagat tgagaaaatc ctcacatttc ggatacccta ctatgtaggc 1920
cccctcgccc ggggaaattc cagattcgcg tggatgactc gcaaatcaga agagaccatc 1980
actccctgga acttcgagga agtcgtggat aagggggcct ctgcccagtc cttcatcgaa 2040
aggatgacta actttgataa aaatctgcct aacgaaaagg tgcttcctaa acactctctg 2100
ctgtacgagt acttcacagt ttataacgag ctcaccaagg tcaaatacgt cacagaaggg 2160
atgagaaagc cagcattcct gtctggagag cagaagaaag ctatcgtgga cctcctcttc 2220
aagacgaacc ggaaagttac cgtgaaacag ctcaaagaag actatttcaa aaagattgaa 2280
tgtttcgact ctgttgaaat cagcggagtg gaggatcgct tcaacgcatc cctgggaacg 2340
tatcacgatc tcctgaaaat cattaaagac aaggacttcc tggacaatga ggagaacgag 2400
gacattcttg aggacattgt cctcaccctt acgttgtttg aagataggga gatgattgaa 2460
gaacgcttga aaacttacgc tcatctcttc gacgacaaag tcatgaaaca gctcaagagg 2520
cgccgatata caggatgggg gcggctgtca agaaaactga tcaatgggat ccgagacaag 2580
cagagtggaa agacaatcct ggattttctt aagtccgatg gatttgccaa ccggaacttc 2640
atgcagttga tccatgatga ctctctcacc tttaaggagg acatccagaa agcacaagtt 2700
tctggccagg gggacagtct tcacgagcac atcgctaatc ttgcaggtag cccagctatc 2760
aaaaagggaa tactgcagac cgttaaggtc gtggatgaac tcgtcaaagt aatgggaagg 2820
cataagcccg agaatatcgt tatcgagatg gcccgagaga accaaactac ccagaaggga 2880
cagaagaaca gtagggaaag gatgaagagg attgaagagg gtataaaaga actggggtcc 2940
caaatcctta aggaacaccc agttgaaaac acccagcttc agaatgagaa gctctacctg 3000
tactacctgc agaacggcag ggacatgtac gtggatcagg aactggacat caatcggctc 3060
tccgactacg acgtggatca tatcgtgccc cagtcttttc tcaaagatga ttctattgat 3120
aataaagtgt tgacaagatc cgataaaaat agagggaaga gtgataacgt cccctcagaa 3180
gaagttgtca agaaaatgaa aaattattgg cggcagctgc tgaacgccaa actgatcaca 3240
caacggaagt tcgataatct gactaaggct gaacgaggtg gcctgtctga gttggataaa 3300
gcaggcttca tcaaaaggca gcttgttgag acacgccaga tcaccaagca cgtggcccaa 3360
attctcgatt cacgcatgaa caccaagtac gatgaaaatg acaaactgat tcgagaggtg 3420
aaagttatta ctctgaagtc taagctggtc tcagatttca gaaaggactt tcagttttat 3480
aaggtgagag agatcaacaa ttaccaccat gcgcatgatg cctacctgaa tgcagtggta 3540
ggcactgcac ttatcaaaaa atatcccaag cttgaatctg aatttgttta cggagactat 3600
aaagtgtacg atgttaggaa aatgatcgca aagtctgagc aggaaatagg caaggccacc 3660
gctaagtact tcttttacag caatattatg aattttttca agaccgagat tacactggcc 3720
aatggagaga ttcggaagcg accacttatc gaaacaaacg gagaaacagg agaaatcgtg 3780
tgggacaagg gtagggattt cgcgacagtc cggaaggtcc tgtccatgcc gcaggtgaac 3840
atcgttaaaa agaccgaagt acagaccgga ggcttctcca aggaaagtat cctcccgaaa 3900
aggaacagcg acaagctgat cgcacgcaaa aaagattggg accccaagaa atacggcgga 3960
ttcgattctc ctacagtcgc ttacagtgta ctggttgtgg ccaaagtgga gaaagggaag 4020
tctaaaaaac tcaaaagcgt caaggaactg ctgggcatca caatcatgga gcgatcaagc 4080
ttcgaaaaaa accccatcga ctttctcgag gcgaaaggat ataaagaggt caaaaaagac 4140
ctcatcatta agcttcccaa gtactctctc tttgagcttg aaaacggccg gaaacgaatg 4200
ctcgctagtg cgggcgagct gcagaaaggt aacgagctgg cactgccctc taaatacgtt 4260
aatttcttgt atctggccag ccactatgaa aagctcaaag ggtctcccga agataatgag 4320
cagaagcagc tgttcgtgga acaacacaaa cactaccttg atgagatcat cgagcaaata 4380
agcgaattct ccaaaagagt gatcctcgcc gacgctaacc tcgataaggt gctttctgct 4440
tacaataagc acagggataa gcccatcagg gagcaggcag aaaacattat ccacttgttt 4500
actctgacca acttgggcgc gcctgcagcc ttcaagtact tcgacaccac catagacaga 4560
aagcggtaca cctctacaaa ggaggtcctg gacgccacac tgattcatca gtcaattacg 4620
gggctctatg aaacaagaat cgacctctct cagctcggtg gagac 4665
<210> 14
<211> 1555
<212> PRT
<213> n
<400> 14
Met Gly Ser Ser His His His His His His Ser Glu Val Glu Phe Ser
1 5 10 15
His Glu Tyr Trp Met Arg His Ala Leu Thr Leu Ala Lys Arg Ala Arg
20 25 30
Asp Glu Arg Glu Val Pro Val Gly Ala Val Leu Val Leu Asn Asn Arg
35 40 45
Val Ile Gly Glu Gly Trp Asn Arg Ala Ile Gly Leu His Asp Pro Thr
50 55 60
Ala His Ala Glu Ile Met Ala Leu Arg Gln Gly Gly Leu Val Met Gln
65 70 75 80
Asn Tyr Arg Leu Ile Asp Ala Thr Leu Tyr Val Thr Phe Glu Pro Cys
85 90 95
Val Met Cys Ala Gly Ala Met Ile His Ser Arg Ile Gly Arg Val Val
100 105 110
Phe Gly Val Arg Asn Ser Lys Arg Gly Ala Ala Gly Ser Leu Met Asn
115 120 125
Val Leu Asn Tyr Pro Gly Met Asn His Arg Val Glu Ile Thr Glu Gly
130 135 140
Ile Leu Ala Asp Glu Cys Ala Ala Leu Leu Cys Asp Phe Tyr Arg Met
145 150 155 160
Pro Arg Gln Val Phe Asn Ala Gln Lys Lys Ala Gln Ser Ser Ile Asn
165 170 175
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala Asp Lys Lys Tyr
180 185 190
Ser Ile Gly Leu Ala Ile Gly Thr Asn Ser Val Gly Trp Ala Val Ile
195 200 205
Thr Asp Glu Tyr Lys Val Pro Ser Lys Lys Phe Lys Val Leu Gly Asn
210 215 220
Thr Asp Arg His Ser Ile Lys Lys Asn Leu Ile Gly Ala Leu Leu Phe
225 230 235 240
Asp Ser Gly Glu Thr Ala Glu Ala Thr Arg Leu Lys Arg Thr Ala Arg
245 250 255
Arg Arg Tyr Thr Arg Arg Lys Asn Arg Ile Cys Tyr Leu Gln Glu Ile
260 265 270
Phe Ser Asn Glu Met Ala Lys Val Asp Asp Ser Phe Phe His Arg Leu
275 280 285
Glu Glu Ser Phe Leu Val Glu Glu Asp Lys Lys His Glu Arg His Pro
290 295 300
Ile Phe Gly Asn Ile Val Asp Glu Val Ala Tyr His Glu Lys Tyr Pro
305 310 315 320
Thr Ile Tyr His Leu Arg Lys Lys Leu Val Asp Ser Thr Asp Lys Ala
325 330 335
Asp Leu Arg Leu Ile Tyr Leu Ala Leu Ala His Met Ile Lys Phe Arg
340 345 350
Gly His Phe Leu Ile Glu Gly Asp Leu Asn Pro Asp Asn Ser Asp Val
355 360 365
Asp Lys Leu Phe Ile Gln Leu Val Gln Thr Tyr Asn Gln Leu Phe Glu
370 375 380
Glu Asn Pro Ile Asn Ala Ser Gly Val Asp Ala Lys Ala Ile Leu Ser
385 390 395 400
Ala Arg Leu Ser Lys Ser Arg Arg Leu Glu Asn Leu Ile Ala Gln Leu
405 410 415
Pro Gly Glu Lys Lys Asn Gly Leu Phe Gly Asn Leu Ile Ala Leu Ser
420 425 430
Leu Gly Leu Thr Pro Asn Phe Lys Ser Asn Phe Asp Leu Ala Glu Asp
435 440 445
Ala Lys Leu Gln Leu Ser Lys Asp Thr Tyr Asp Asp Asp Leu Asp Asn
450 455 460
Leu Leu Ala Gln Ile Gly Asp Gln Tyr Ala Asp Leu Phe Leu Ala Ala
465 470 475 480
Lys Asn Leu Ser Asp Ala Ile Leu Leu Ser Asp Ile Leu Arg Val Asn
485 490 495
Thr Glu Ile Thr Lys Ala Pro Leu Ser Ala Ser Met Ile Lys Arg Tyr
500 505 510
Asp Glu His His Gln Asp Leu Thr Leu Leu Lys Ala Leu Val Arg Gln
515 520 525
Gln Leu Pro Glu Lys Tyr Lys Glu Ile Phe Phe Asp Gln Ser Lys Asn
530 535 540
Gly Tyr Ala Gly Tyr Ile Asp Gly Gly Ala Ser Gln Glu Glu Phe Tyr
545 550 555 560
Lys Phe Ile Lys Pro Ile Leu Glu Lys Met Asp Gly Thr Glu Glu Leu
565 570 575
Leu Val Lys Leu Asn Arg Glu Asp Leu Leu Arg Lys Gln Arg Thr Phe
580 585 590
Asp Asn Gly Ser Ile Pro His Gln Ile His Leu Gly Glu Leu His Ala
595 600 605
Ile Leu Arg Arg Gln Glu Asp Phe Tyr Pro Phe Leu Lys Asp Asn Arg
610 615 620
Glu Lys Ile Glu Lys Ile Leu Thr Phe Arg Ile Pro Tyr Tyr Val Gly
625 630 635 640
Pro Leu Ala Arg Gly Asn Ser Arg Phe Ala Trp Met Thr Arg Lys Ser
645 650 655
Glu Glu Thr Ile Thr Pro Trp Asn Phe Glu Glu Val Val Asp Lys Gly
660 665 670
Ala Ser Ala Gln Ser Phe Ile Glu Arg Met Thr Asn Phe Asp Lys Asn
675 680 685
Leu Pro Asn Glu Lys Val Leu Pro Lys His Ser Leu Leu Tyr Glu Tyr
690 695 700
Phe Thr Val Tyr Asn Glu Leu Thr Lys Val Lys Tyr Val Thr Glu Gly
705 710 715 720
Met Arg Lys Pro Ala Phe Leu Ser Gly Glu Gln Lys Lys Ala Ile Val
725 730 735
Asp Leu Leu Phe Lys Thr Asn Arg Lys Val Thr Val Lys Gln Leu Lys
740 745 750
Glu Asp Tyr Phe Lys Lys Ile Glu Cys Phe Asp Ser Val Glu Ile Ser
755 760 765
Gly Val Glu Asp Arg Phe Asn Ala Ser Leu Gly Thr Tyr His Asp Leu
770 775 780
Leu Lys Ile Ile Lys Asp Lys Asp Phe Leu Asp Asn Glu Glu Asn Glu
785 790 795 800
Asp Ile Leu Glu Asp Ile Val Leu Thr Leu Thr Leu Phe Glu Asp Arg
805 810 815
Glu Met Ile Glu Glu Arg Leu Lys Thr Tyr Ala His Leu Phe Asp Asp
820 825 830
Lys Val Met Lys Gln Leu Lys Arg Arg Arg Tyr Thr Gly Trp Gly Arg
835 840 845
Leu Ser Arg Lys Leu Ile Asn Gly Ile Arg Asp Lys Gln Ser Gly Lys
850 855 860
Thr Ile Leu Asp Phe Leu Lys Ser Asp Gly Phe Ala Asn Arg Asn Phe
865 870 875 880
Met Gln Leu Ile His Asp Asp Ser Leu Thr Phe Lys Glu Asp Ile Gln
885 890 895
Lys Ala Gln Val Ser Gly Gln Gly Asp Ser Leu His Glu His Ile Ala
900 905 910
Asn Leu Ala Gly Ser Pro Ala Ile Lys Lys Gly Ile Leu Gln Thr Val
915 920 925
Lys Val Val Asp Glu Leu Val Lys Val Met Gly Arg His Lys Pro Glu
930 935 940
Asn Ile Val Ile Glu Met Ala Arg Glu Asn Gln Thr Thr Gln Lys Gly
945 950 955 960
Gln Lys Asn Ser Arg Glu Arg Met Lys Arg Ile Glu Glu Gly Ile Lys
965 970 975
Glu Leu Gly Ser Gln Ile Leu Lys Glu His Pro Val Glu Asn Thr Gln
980 985 990
Leu Gln Asn Glu Lys Leu Tyr Leu Tyr Tyr Leu Gln Asn Gly Arg Asp
995 1000 1005
Met Tyr Val Asp Gln Glu Leu Asp Ile Asn Arg Leu Ser Asp Tyr Asp
1010 1015 1020
Val Asp His Ile Val Pro Gln Ser Phe Leu Lys Asp Asp Ser Ile Asp
1025 1030 1035 1040
Asn Lys Val Leu Thr Arg Ser Asp Lys Asn Arg Gly Lys Ser Asp Asn
1045 1050 1055
Val Pro Ser Glu Glu Val Val Lys Lys Met Lys Asn Tyr Trp Arg Gln
1060 1065 1070
Leu Leu Asn Ala Lys Leu Ile Thr Gln Arg Lys Phe Asp Asn Leu Thr
1075 1080 1085
Lys Ala Glu Arg Gly Gly Leu Ser Glu Leu Asp Lys Ala Gly Phe Ile
1090 1095 1100
Lys Arg Gln Leu Val Glu Thr Arg Gln Ile Thr Lys His Val Ala Gln
1105 1110 1115 1120
Ile Leu Asp Ser Arg Met Asn Thr Lys Tyr Asp Glu Asn Asp Lys Leu
1125 1130 1135
Ile Arg Glu Val Lys Val Ile Thr Leu Lys Ser Lys Leu Val Ser Asp
1140 1145 1150
Phe Arg Lys Asp Phe Gln Phe Tyr Lys Val Arg Glu Ile Asn Asn Tyr
1155 1160 1165
His His Ala His Asp Ala Tyr Leu Asn Ala Val Val Gly Thr Ala Leu
1170 1175 1180
Ile Lys Lys Tyr Pro Lys Leu Glu Ser Glu Phe Val Tyr Gly Asp Tyr
1185 1190 1195 1200
Lys Val Tyr Asp Val Arg Lys Met Ile Ala Lys Ser Glu Gln Glu Ile
1205 1210 1215
Gly Lys Ala Thr Ala Lys Tyr Phe Phe Tyr Ser Asn Ile Met Asn Phe
1220 1225 1230
Phe Lys Thr Glu Ile Thr Leu Ala Asn Gly Glu Ile Arg Lys Arg Pro
1235 1240 1245
Leu Ile Glu Thr Asn Gly Glu Thr Gly Glu Ile Val Trp Asp Lys Gly
1250 1255 1260
Arg Asp Phe Ala Thr Val Arg Lys Val Leu Ser Met Pro Gln Val Asn
1265 1270 1275 1280
Ile Val Lys Lys Thr Glu Val Gln Thr Gly Gly Phe Ser Lys Glu Ser
1285 1290 1295
Ile Leu Pro Lys Arg Asn Ser Asp Lys Leu Ile Ala Arg Lys Lys Asp
1300 1305 1310
Trp Asp Pro Lys Lys Tyr Gly Gly Phe Asp Ser Pro Thr Val Ala Tyr
1315 1320 1325
Ser Val Leu Val Val Ala Lys Val Glu Lys Gly Lys Ser Lys Lys Leu
1330 1335 1340
Lys Ser Val Lys Glu Leu Leu Gly Ile Thr Ile Met Glu Arg Ser Ser
1345 1350 1355 1360
Phe Glu Lys Asn Pro Ile Asp Phe Leu Glu Ala Lys Gly Tyr Lys Glu
1365 1370 1375
Val Lys Lys Asp Leu Ile Ile Lys Leu Pro Lys Tyr Ser Leu Phe Glu
1380 1385 1390
Leu Glu Asn Gly Arg Lys Arg Met Leu Ala Ser Ala Gly Glu Leu Gln
1395 1400 1405
Lys Gly Asn Glu Leu Ala Leu Pro Ser Lys Tyr Val Asn Phe Leu Tyr
1410 1415 1420
Leu Ala Ser His Tyr Glu Lys Leu Lys Gly Ser Pro Glu Asp Asn Glu
1425 1430 1435 1440
Gln Lys Gln Leu Phe Val Glu Gln His Lys His Tyr Leu Asp Glu Ile
1445 1450 1455
Ile Glu Gln Ile Ser Glu Phe Ser Lys Arg Val Ile Leu Ala Asp Ala
1460 1465 1470
Asn Leu Asp Lys Val Leu Ser Ala Tyr Asn Lys His Arg Asp Lys Pro
1475 1480 1485
Ile Arg Glu Gln Ala Glu Asn Ile Ile His Leu Phe Thr Leu Thr Asn
1490 1495 1500
Leu Gly Ala Pro Ala Ala Phe Lys Tyr Phe Asp Thr Thr Ile Asp Arg
1505 1510 1515 1520
Lys Arg Tyr Thr Ser Thr Lys Glu Val Leu Asp Ala Thr Leu Ile His
1525 1530 1535
Gln Ser Ile Thr Gly Leu Tyr Glu Thr Arg Ile Asp Leu Ser Gln Leu
1540 1545 1550
Gly Gly Asp
1555
<210> 15
<211> 37
<212> DNA
<213> of
<400> 15
gaaacccgca gcgataagaa atactcaata ggcttag 37
<210> 16
<211> 37
<212> DNA
<213> or
<400> 16
gctgcgggtt tcgttaatgg aagattgagc cttcttc 37
<210> 17
<211> 37
<212> DNA
<213> pf
<400> 17
ccggcgccgg cggataagaa atactcaata ggcttag 37
<210> 18
<211> 37
<212> DNA
<213> or
<400> 18
cgccggcgcc gggttaatgg aagattgagc cttcttc 37
<210> 19
<211> 43
<212> DNA
<213> pf
<400> 19
aacaaaacct atccgccgga taagaaatac tcaataggct tag 43
<210> 20
<211> 43
<212> DNA
<213> pr
<400> 20
cggcggatag gttttgttgt taatggaaga ttgagccttc ttc 43
<210> 21
<211> 36
<212> DNA
<213> qf
<400> 21
accaccgaac cgataagaaa tactcaatag gcttag 36
<210> 22
<211> 36
<212> DNA
<213> qr
<400> 22
ggttcggtgg tgttaatgga agattgagcc ttcttc 36
<210> 23
<211> 36
<212> DNA
<213> qff
<400> 23
gccggataac gataagaaat actcaatagg cttagc 36
<210> 24
<211> 36
<212> DNA
<213> qrr
<400> 24
gttatccggc ggttcggtgg tgttaatgga agattg 36
<210> 25
<211> 36
<212> DNA
<213> rf
<400> 25
ccggcgccgg cgataagaaa tactcaatag gcttag 36
<210> 26
<211> 36
<212> DNA
<213> rr
<400> 26
gccggcgccg ggttaatgga agattgagcc ttcttc 36
<210> 27
<211> 35
<212> DNA
<213> rff
<400> 27
gccggcgccg gataagaaat actcaatagg cttag 35
<210> 28
<211> 35
<212> DNA
<213> rrr
<400> 28
cggcgccggc gccggcgccg ggttaatgga agatt 35
<210> 29
<211> 43
<212> DNA
<213> sf
<400> 29
gaagcggcgg cgaaagcgga taagaaatac tcaataggct tag 43
<210> 30
<211> 43
<212> DNA
<213> sr
<400> 30
cgctttcgcc gccgcttcgt taatggaaga ttgagccttc ttc 43
<210> 31
<211> 42
<212> DNA
<213> sff
<400> 31
gcggaagcgg cggcgaaaga agcggcggcg aaagcggata ag 42
<210> 32
<211> 43
<212> DNA
<213> srr
<400> 32
tttcgccgcc gcttccgcgt taatggaaga ttgagccttc ttc 43
<210> 33
<211> 920
<212> DNA
<213> t
<400> 33
tagtcctgtc gggtttcgcc acctctgact tgagcgtcga tttttgtgat gctcgtcagg 60
ggggcggagc ctatggaaaa acgccagcaa cgcggccttt ttacggttcc tggccttttg 120
ctggcctttt gctcacatgt tctttcctgc gttatcccct gattctgtgg ataaccgtat 180
taccgccttt gagtgagctg ataccgctcg ccgcagccga acgaccgagc gcagcgagtc 240
agtgagcgag gaagcggaag agcgcccaat acgcaaaccg cctctccccg cgcgttggcc 300
gattcattaa tgcagctggc acgacaggtt tcccgactgg aaagcgggca gtgagcgcaa 360
cgcaattaat gtgagttagc tcactcatta ggcaccccag gctttacact ttatgcttcc 420
ggctcgtatg ttgtgtggaa ttgtgagcgg ataacaattt cacacaggaa acagctatga 480
ccatgattac gccaagctcg aaattaaccc tcactaaagg gaacaaaagc tggagctcca 540
ccgcggtggc ggccgctcta gaactagtgg atcccccggg ctgcaggaat tcgatatcaa 600
gcttatcgat gttacccttt ctttgtctgt aggttagagc tagaaatagc aagttaaaat 660
aaggctagtc cgttatcaac ttgaaaaagt ggcaccgagt cggtgctctc gagggggggc 720
ccggtaccca attcgcccta tagtgagtcg tattacaatt cactggccgt cgttttacaa 780
cgtcgtgact gggaaaaccc tggcgttacc caacttaatc gccttgcagc acatccccct 840
ttcgccagct ggcgtaatag cgaagaggcc cgcaccgatc gcccttccca acagttgcgc 900
agcctgaatg gcgaatggaa 920
<210> 34
<211> 920
<212> DNA
<213> u
<400> 34
tagtcctgtc gggtttcgcc acctctgact tgagcgtcga tttttgtgat gctcgtcagg 60
ggggcggagc ctatggaaaa acgccagcaa cgcggccttt ttacggttcc tggccttttg 120
ctggcctttt gctcacatgt tctttcctgc gttatcccct gattctgtgg ataaccgtat 180
taccgccttt gagtgagctg ataccgctcg ccgcagccga acgaccgagc gcagcgagtc 240
agtgagcgag gaagcggaag agcgcccaat acgcaaaccg cctctccccg cgcgttggcc 300
gattcattaa tgcagctggc acgacaggtt tcccgactgg aaagcgggca gtgagcgcaa 360
cgcaattaat gtgagttagc tcactcatta ggcaccccag gctttacact ttatgcttcc 420
ggctcgtatg ttgtgtggaa ttgtgagcgg ataacaattt cacacaggaa acagctatga 480
ccatgattac gccaagctcg aaattaaccc tcactaaagg gaacaaaagc tggagctcca 540
ccgcggtggc ggccgctcta gaactagtgg atcccccggg ctgcaggaat tcgatatcaa 600
gcttatcgat gttcaccttt ctttgtctgt aggttagagc tagaaatagc aagttaaaat 660
aaggctagtc cgttatcaac ttgaaaaagt ggcaccgagt cggtgctctc gagggggggc 720
ccggtaccca attcgcccta tagtgagtcg tattacaatt cactggccgt cgttttacaa 780
cgtcgtgact gggaaaaccc tggcgttacc caacttaatc gccttgcagc acatccccct 840
ttcgccagct ggcgtaatag cgaagaggcc cgcaccgatc gcccttccca acagttgcgc 900
agcctgaatg gcgaatggaa 920
<210> 35
<211> 920
<212> DNA
<213> v
<400> 35
tagtcctgtc gggtttcgcc acctctgact tgagcgtcga tttttgtgat gctcgtcagg 60
ggggcggagc ctatggaaaa acgccagcaa cgcggccttt ttacggttcc tggccttttg 120
ctggcctttt gctcacatgt tctttcctgc gttatcccct gattctgtgg ataaccgtat 180
taccgccttt gagtgagctg ataccgctcg ccgcagccga acgaccgagc gcagcgagtc 240
agtgagcgag gaagcggaag agcgcccaat acgcaaaccg cctctccccg cgcgttggcc 300
gattcattaa tgcagctggc acgacaggtt tcccgactgg aaagcgggca gtgagcgcaa 360
cgcaattaat gtgagttagc tcactcatta ggcaccccag gctttacact ttatgcttcc 420
ggctcgtatg ttgtgtggaa ttgtgagcgg ataacaattt cacacaggaa acagctatga 480
ccatgattac gccaagctcg aaattaaccc tcactaaagg gaacaaaagc tggagctcca 540
ccgcggtggc ggccgctcta gaactagtgg atcccccggg ctgcaggaat tcgatatcaa 600
gcttatcgat gttccacttt ctttgtctgt aggttagagc tagaaatagc aagttaaaat 660
aaggctagtc cgttatcaac ttgaaaaagt ggcaccgagt cggtgctctc gagggggggc 720
ccggtaccca attcgcccta tagtgagtcg tattacaatt cactggccgt cgttttacaa 780
cgtcgtgact gggaaaaccc tggcgttacc caacttaatc gccttgcagc acatccccct 840
ttcgccagct ggcgtaatag cgaagaggcc cgcaccgatc gcccttccca acagttgcgc 900
agcctgaatg gcgaatggaa 920
<210> 36
<211> 920
<212> DNA
<213> w
<400> 36
tagtcctgtc gggtttcgcc acctctgact tgagcgtcga tttttgtgat gctcgtcagg 60
ggggcggagc ctatggaaaa acgccagcaa cgcggccttt ttacggttcc tggccttttg 120
ctggcctttt gctcacatgt tctttcctgc gttatcccct gattctgtgg ataaccgtat 180
taccgccttt gagtgagctg ataccgctcg ccgcagccga acgaccgagc gcagcgagtc 240
agtgagcgag gaagcggaag agcgcccaat acgcaaaccg cctctccccg cgcgttggcc 300
gattcattaa tgcagctggc acgacaggtt tcccgactgg aaagcgggca gtgagcgcaa 360
cgcaattaat gtgagttagc tcactcatta ggcaccccag gctttacact ttatgcttcc 420
ggctcgtatg ttgtgtggaa ttgtgagcgg ataacaattt cacacaggaa acagctatga 480
ccatgattac gccaagctcg aaattaaccc tcactaaagg gaacaaaagc tggagctcca 540
ccgcggtggc ggccgctcta gaactagtgg atcccccggg ctgcaggaat tcgatatcaa 600
gcttatcgat gttcccattt ctttgtctgt aggttagagc tagaaatagc aagttaaaat 660
aaggctagtc cgttatcaac ttgaaaaagt ggcaccgagt cggtgctctc gagggggggc 720
ccggtaccca attcgcccta tagtgagtcg tattacaatt cactggccgt cgttttacaa 780
cgtcgtgact gggaaaaccc tggcgttacc caacttaatc gccttgcagc acatccccct 840
ttcgccagct ggcgtaatag cgaagaggcc cgcaccgatc gcccttccca acagttgcgc 900
agcctgaatg gcgaatggaa 920
<210> 37
<211> 920
<212> DNA
<213> x
<400> 37
tagtcctgtc gggtttcgcc acctctgact tgagcgtcga tttttgtgat gctcgtcagg 60
ggggcggagc ctatggaaaa acgccagcaa cgcggccttt ttacggttcc tggccttttg 120
ctggcctttt gctcacatgt tctttcctgc gttatcccct gattctgtgg ataaccgtat 180
taccgccttt gagtgagctg ataccgctcg ccgcagccga acgaccgagc gcagcgagtc 240
agtgagcgag gaagcggaag agcgcccaat acgcaaaccg cctctccccg cgcgttggcc 300
gattcattaa tgcagctggc acgacaggtt tcccgactgg aaagcgggca gtgagcgcaa 360
cgcaattaat gtgagttagc tcactcatta ggcaccccag gctttacact ttatgcttcc 420
ggctcgtatg ttgtgtggaa ttgtgagcgg ataacaattt cacacaggaa acagctatga 480
ccatgattac gccaagctcg aaattaaccc tcactaaagg gaacaaaagc tggagctcca 540
ccgcggtggc ggccgctcta gaactagtgg atcccccggg ctgcaggaat tcgatatcaa 600
gcttatcgat gttctccatt ctttgtctgt aggttagagc tagaaatagc aagttaaaat 660
aaggctagtc cgttatcaac ttgaaaaagt ggcaccgagt cggtgctctc gagggggggc 720
ccggtaccca attcgcccta tagtgagtcg tattacaatt cactggccgt cgttttacaa 780
cgtcgtgact gggaaaaccc tggcgttacc caacttaatc gccttgcagc acatccccct 840
ttcgccagct ggcgtaatag cgaagaggcc cgcaccgatc gcccttccca acagttgcgc 900
agcctgaatg gcgaatggaa 920
<210> 38
<211> 115
<212> DNA
<213> y
<400> 38
uaauacgacu cacuauaggg uuacccuuuc uuugucugug uuuuagagcu agaaauagca 60
aguuaaaaua aggcuagucc guuaucaacu ugaaaaagug gcaccgaguc ggugc 115
<210> 39
<211> 115
<212> DNA
<213> yy
<400> 39
uaauacgacu cacuauaggg uucaccuuuc uuugucugug uuuuagagcu agaaauagca 60
aguuaaaaua aggcuagucc guuaucaacu ugaaaaagug gcaccgaguc ggugc 115
<210> 40
<211> 115
<212> DNA
<213> yyy
<400> 40
uaauacgacu cacuauaggg uuccacuuuc uuugucugug uuuuagagcu agaaauagca 60
aguuaaaaua aggcuagucc guuaucaacu ugaaaaagug gcaccgaguc ggugc 115
<210> 41
<211> 115
<212> DNA
<213> yyyy
<400> 41
uaauacgacu cacuauaggg uucccauuuc uuugucugug uuuuagagcu agaaauagca 60
aguuaaaaua aggcuagucc guuaucaacu ugaaaaagug gcaccgaguc ggugc 115
<210> 42
<211> 115
<212> DNA
<213> yyyyy
<400> 42
uaauacgacu cacuauaggg uucuccauuc uuugucugug uuuuagagcu agaaauagca 60
aguuaaaaua aggcuagucc guuaucaacu ugaaaaagug gcaccgaguc ggugc 115

Claims (9)

1. A high-precision adenine base editor is characterized in that a linker of 32 amino acids of wild ABE8e, namely 177 to 208 amino acids, is respectively replaced by ETRS, NKTYPP, TTEPPDN, PAPA, PAPAPAP and A (EAAAK)2The recombinant protein is obtained after A and is sequentially marked as 4L-ABE8e, 4P-ABE8e, 6L-ABE8e, 7L-ABE8e, 7P-ABE8e and 12EK-ABE8 e; the nucleotide sequences are respectively shown in SEQ ID NO.3, SEQ ID NO.5, SEQ ID NO.7, SEQ ID NO.9, SEQ ID NO.11 and SEQ ID NO.13, and the amino acid sequences are respectively shown in SEQ ID NO.4, SEQ ID NO.6, SEQ ID NO.8, SEQ ID NO.10, SEQ ID NO.12 and SEQ ID NO. 14.
2. An expression vector comprising the polynucleotide sequence of claim 1.
3. A host cell for transformation of the expression vector of claim 2.
4. The method for preparing six high-precision adenine base editors as claimed in claim 1, comprising the steps of: firstly, constructing a polynucleotide sequence expression vector of claim 2; then, transforming the expression vector into the host cell according to claim 3, screening and picking out a single clone; and finally, inducing and expressing the monoclone, and separating the six high-precision adenine base editors from an expression product by an affinity chromatography and molecular sieve method.
5. Use of the high precision adenine base editor of claim 1 or the expression vector of claim 2 as an editing tool for editing genomic DNA in the editing of genomic DNA fragments in association therewith.
6. The use of claim 5, wherein said gene editing is multi-site editing with more than two editing sites; the means for editing is base conversion of adenine (A) to guanine (G).
7. The use of claim 6, characterized in that six high precision adenine base editors, 4L-ABE8e, 4P-ABE8e, 6L-ABE8e, 7L-ABE8e, 7P-ABE8e and 12EK-ABE8e, are used as editing tools, including guide sgRNA matched to target DNA fragments; the six high-precision adenine base editors can be combined with sgRNAs which mediate the six high-precision adenine base editors to edit target genes.
8. The use according to claim 7, wherein the expression vector is transformed into a host cell with a guide sgRNA matched thereto to edit a gene.
9. The use according to claim 7, wherein the base transition from adenine (A) to guanine (G) at the multiple site is a deamination of adenine (A) using an adenine base editor and a repair of mismatches between the strands by a repair system of the host cell, thereby converting the base from adenine (A) to guanine (G).
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